Module 4: ROL Annotated Bibliography

My topic is the prevalence of medicine resistance in oncology.

Guidelines for Assignment:

A Review of Literature is conducted to generate an understanding of what is known and not known about a topic of interest. You have identified a topic/problem in Module 1 Discussion Board – Research Problem and found three related study articles in Module 4. In this assignment, you will create an annotated bibliography of study articles as part of a Review of Literature following the guidelines in Gray & Grove, (2021) and share your review.  Submit your Annotated Bibliography as one paper (as a Word Docx) to the assignment link first,  and then your three articles in pdf format. Use the Template below to assist your writing.

REVIEW
published: 23 June 2022
doi: 10.3389/fonc.2022.877380
Cross-Resistance Among
Sequential Cancer Therapeutics:
An Emerging Issue
Rossella Loria 1, Patrizia Vici 2, Francesca Sofia Di Lisa 2,3, Silvia Soddu 1,
Marcello Maugeri-Saccà 4 and Giulia Bon 1*
1 Cellular Network and Molecular Therapeutic Target Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy, 2 Unit
of Phase IV Trials, IRCCS Regina Elena National Cancer Institute, Rome, Italy, 3 Medical Oncology A, Department of
Radiological, Oncological, and Anatomo-Pathological Sciences, Umberto I University Hospital, University Sapienza, Rome, Italy,
4 Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
Edited by:
Petranel T. Ferrao,
Independent Researcher, Adelaide,
SA, Australia
Reviewed by:
Fabiana Napolitano,
University of Naples Federico II, Italy
Parth Sarthi Sen Gupta,
Indian Institute of Science Education
and Research Berhampur
(IISER), India
Steven De Jong,
University Medical Center Groningen,
Netherlands
*Correspondence:
Giulia Bon
giulia.bon@ifo.it
Specialty section:
This article was submitted to
Molecular and Cellular Oncology,
a section of the journal
Frontiers in Oncology
Received: 16 February 2022
Accepted: 04 May 2022
Published: 23 June 2022
Citation:
Loria R, Vici P, Di Lisa FS,
Soddu S, Maugeri-Saccà M and
Bon G (2022) Cross-Resistance
Among Sequential Cancer
Therapeutics: An Emerging Issue.
Front. Oncol. 12:877380.
doi: 10.3389/fonc.2022.877380
Frontiers in Oncology | www.frontiersin.org
Over the past two decades, cancer treatment has benefited from having a significant
increase in the number of targeted drugs approved by the United States Food and Drug
Administration. With the introduction of targeted therapy, a great shift towards a new era
has taken place that is characterized by reduced cytotoxicity and improved clinical
outcomes compared to traditional chemotherapeutic drugs. At present, targeted
therapies and other systemic anti-cancer therapies available (immunotherapy, cytotoxic,
endocrine therapies and others) are used alone or in combination in different settings
(neoadjuvant, adjuvant, and metastatic). As a result, it is not uncommon for patients
affected by an advanced malignancy to receive subsequent anti-cancer therapies. In this
challenging complexity of cancer treatment, the clinical pathways of real-life patients are
often not as direct as predicted by standard guidelines and clinical trials, and crossresistance among sequential anti-cancer therapies represents an emerging issue. In this
review, we summarize the main cross-resistance events described in the diverse tumor
types and provide insight into the molecular mechanisms involved in this process. We also
discuss the current challenges and provide perspectives for the research and
development of strategies to overcome cross-resistance and proceed towards a
personalized approach.
Keywords: targeted-therapy, cancer therapeutics resistance, cross-resistance, sequential therapeutics,
personalized oncology
INTRODUCTION
The history of targeted cancer therapy started in the 1970s with the approval of tamoxifen, the first
selective estrogen receptor (ER) modulator (1). At the beginning of the ‘80s, advances in molecular
biology allowed to identify new molecular targets involved in neoplastic transformation and progression.
These discoveries sparked a revolution in cancer therapy, at the time mainly based on combination
chemotherapy regimens, that culminated in the development of targeted monoclonal antibodies (mAbs)
and selective protein kinase small molecule inhibitors (PKIs) (2). Following the development of
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Cross-Resistance in Cancer Therapy
hybridoma technology by George Köhler and Cèsar Milstein in
1975 (3), who were awarded a Nobel prize for their discoveries in
1984, several attempts to develop murine mAbs against myelo- and
lympho-proliferative diseases and lymphomas did not give the
expected results (4, 5). In 1986 the United States (U.S.) Food and
Drug Administration (FDA) approved the first therapeutic mAb,
muromonab-CD3, which was to be used as an immunosuppressive
for prevention of transplant rejection (6). At the beginning of the
‘90s, growing scientific and industrial interest in developing targeted
drugs ushered us into an era characterized by the approval of an
increasing number of MAbs and PKIs. The first tyrosine-kinase
inhibitor (TKI), Imatinib mesylate, directed towards the fusion
protein BCR-ABL, obtained approval by the FDA in 2001 (7).
Since then, more than 70 PKIs have been introduced (8), and 100
mAbs have been approved by April 2021, with GlaxoSmithKline’s
Programmed cell Death protein 1 (PD1) blocker dostarlimab (9).
More recently, checkpoint inhibitory mAbs and chimeric antigenspecific receptor (CAR)-transfected T-cells (CAR-T cells) have also
had impact in the oncology field (10).
Targeted cancer therapy has provided huge benefits in terms
of improved response and survival rates as well as reduced side
effects compared to traditional chemotherapy. However, one of
the greatest drawbacks to all currently available cancer therapies
is the emergence of drug resistance leading to tumor progression
(11). For this reason, many patients affected by advanced
malignancy receive sequential anti-cancer therapies, which may
include chemotherapy, immunotherapy, targeted therapy,
endocrine therapy, or a combination of them. The complexity
requires strict criteria to define and enumerate the sequential
lines of therapy uniformly across solid malignancies (12). From a
mechanistic point of view, recent high-throughput sequencing
studies and quantitative modeling approaches have revealed
extensive intratumor heterogeneity and highly dynamic tumor
clonal evolution under the selective pressure exerted by drug
treatments (13–15). It is therefore easy to anticipate that the
evolutionary trajectories imposed by drugs may intersect
through subsequent lines of treatment in unpredictable ways.
In this scenario, the probability that cross-resistance emerges
between sequential treatments increases with a higher number of
therapeutic possibilities. Unfortunately, the current adoption of
sequential lines of therapy according to guidelines is a strategy
that does not consider cross-resistance as well as the possible
development of new targetable vulnerabilities (16).
In this review, we summarize the main known events of crossresistance and the molecular mechanisms involved. We also provide
an overview of real-world data (RWD) as a tool to address the
complexity of cancer therapy, and the possible strategies to adopt in
an attempt to overcome or prevent cross-resistance.
overlapping working mechanisms, such as receptor tyrosine
kinase erbB-2 (HER2)-targeting agents trastuzumab+pertuzumab
and trastuzumab-emtansine (T-DM1) in breast cancer (BC). In this
case, T-DM1 second line treatment might have reduced efficacy. In
a more complex scenario, the characterization of tumor evolution in
terms of clonal selection during therapy has revealed that under
prolonged drug exposure, cancer cells enter a drug-tolerant state
known as drug tolerant persister cells (DTPCs) (17). At this stage,
the activation of heterogeneous mechanisms of drug resistance
causes these subclones to expand and generate stable resistant cell
populations (17–19). The sensitivity of these populations to
subsequent drugs is difficult to predict unless biomarkers will be
defined to represent specific collateral trajectories. The main events
of cross-resistance described thus far for the different types of
targeted therapies are reported below.
Chemotherapeutic Drugs
The use of cytotoxic/cytostatic chemotherapy was the first
approach adopted in the treatment of tumors. However, the
effectiveness of these drugs was often limited by the emergence of
multiple drug resistance (MDR) (20) which determined crossresistance to diverse structurally and functionally unrelated
chemotherapeutic agents.
Although cancer cells develop various mechanisms to escape
chemotherapy, drug transporters belonging to ATP-binding
cassette (ABC) family are the main players implicated in MDR.
These ATP-dependent efflux pumps actively remove drugs from
cancer cells (21). Glycoprotein P (P-gp) is the most relevant ABC
drug transporter. It is encoded by the multidrug resistance
protein 1 gene (MDR1, ABCB1) and overexpressed in over 50%
of cancers with a MDR phenotype (22). P-gp overexpression has
been implicated in resistance to approximately 20 different
cytotoxic drugs including doxorubicin, paclitaxel and related
taxane drugs (23). Many anticancer drugs have been reported to
induce the up-regulation of Forkhead Box O3 (FOXO3A), a
transcription factor closely implicated in MDR, that in turn
enhances ABCB1 transcription and P-gp expression (24).
Other ABC family members involved in MDR include Breast
Cancer Resistance Protein (BCRP; also known as mitoxantrone
resistance protein, MXR), and multidrug resistance-associated
proteins (MRPs) (25). BCRP (encoded by the ABCG2 gene) is the
second most relevant drug transporter. Its overexpression has
been described in many cancers including breast and ovarian and
is associated with resistance to mitoxantrone and topotecan (26,
27). MRPs include MRP1 and MRP2 (also known as MDRrelated protein 1 and MDR-related protein 2) encoded
respectively by the ABCC1 and ABCC2 genes (21, 25, 28). The
drug resistance spectra of MRP1 is similar to that of P-gp except
for taxanes, while MRP2 confers resistance to MRP1 substrates
and cisplatin, one of the most frequently used drugs in cancer
therapy (23, 26).
DNA damage repair (DDR) genes have been implicated in the
cross-resistance among chemotherapeutic drugs. In multiple
mouse models of NSCLC, prolonged cisplatin treatment
promoted the emergence of resistant tumors that were crossresistant to platinum analogs. These cisplatin-resistant tumors
showed enhanced DNA repair capacity due to elevated levels of
CROSS-RESISTANCE AMONG
CANCER THERAPEUTICS
Cross-resistance occurs when acquired resistance induced by a
drug treatment results in resistance to other drugs (Figure 1). It
may occur in the sequential administration of agents with
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Cross-Resistance in Cancer Therapy
A
B
FIGURE 1 | Models of cross–resistance. (A) When drugs acting on the same target are sequentially administered, the first drug can induce target deregulation or
mutation that causes escape from therapy and cross–resistance to the subsequent drug. (B) Cancer therapy promotes evolutionary dynamics fostering mutations,
protein or pathway activity deregulations, and changes in gene expression states that can determine cross–resistance to the next treatment.
Since the approval of trastuzumab, the first anti-HER2 agent
(34) for BC treatment in 1998, an array of other anti-HER2 agents,
such as pertuzumab, lapatinib, T-DM1, and trastuzumabDeruxtecan (T-Dxd) mAb-drug conjugates (ADCs) and others
have been approved, significantly improving the outcome of BC
patients (Figure 2). In addition, a widening arsenal of novel HER2targeting drugs are under development (35). Anti-HER2 treatments
are administered in neoadjuvant, adjuvant, and advanced settings of
BC patients. However, there is a growing body of evidence
suggesting that HER2-targeted treatment may significantly
influence the loss/reduction of HER2 expression (36–47).
Mittendorf and colleagues have described the loss of HER2
amplification in residual disease in 32% of BC patients treated
with neoadjuvant trastuzumab in combination with anthracyclines
and taxanes, as this change is associated with poor recurrence-free
survival (43). In a retrospective cohort study involving 21,755
Japanese BC patients, loss of HER2 was observed in 20.4%
following neoadjuvant trastuzumab (44). In the advanced setting,
Ignatov and colleagues have shown that loss of HER2 is associated
with previous HER2-targeted treatment and reduced disease-free
survival. Interestingly, a change in HER2 expression was observed in
multiple DDR-related genes (29). In support of these findings,
the DNA repair capacity measured in peripheral lymphocytes is
an independent predictor of survival for non-small cell lung
cancer (NSCLC) patients treated with platinum-based
chemotherapy (30) and the inhibition of DNA repair kinases
could also prevent doxorubicin resistance in BC cells (31).
Furthermore, DDR pathways can be enhanced in cancer cells
providing a survival advantage after chemotherapy (32).
HER2- and Estrogen
Receptor-Targeted Therapies
HER2 is a member of the Epidermal Growth Factor Receptor
(EGFR) family of receptor tyrosine kinases. HER2 amplification
and/or overexpression have been described in BC (20% of cases)
and in a variety of other solid tumors, including gastric cancer
(GC, 20%), biliary tract cancer (BTC, 20%), bladder cancer (BlC,
12.5%), colorectal cancer (CRC, 5%) and NSCLC (2.5%) (33).
Although HER2 is an established therapeutic target in a subset of
women with BC, the early HER2-targeted therapies have not
proven to be as effective in HER2-positive (HER2+) GC or other
solid tumors.
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FIGURE 2 | Mechanism of action of HER2–, ER–, and CDK4/6–targeted drugs. HER family RTKs (EGFR, HER2, and HER3) activate several oncogenic signaling
pathways such as Ras/Raf/MEK/ERK or PI3K/Akt/mTOR to stimulate growth and proliferation. Direct HER2 inhibitors include trastuzumab and the conjugates of
trastuzumab with DM1 (T–DM1) or Dxd (T–Dxd). In the case of drug–antibody conjugates, upon binding of trastuzumab to HER2, the payload is internalized by
endocytosis to induce DNA damage. Pertuzumab mAb binds HER2, preventing homodimerization and heterodimerization with other family members, especially
HER3. Lapatinib is a EGFR/HER2 TKI that attenuates cell proliferation, cell–cycle regulation, and downstream pathways. Tucatinib is a selective HER2 TKI with
minimal inhibition of EGFR. Neratinib is a pan–HER irreversible TKI. ER is a transcription factor which, under estrogen stimulation, is recruited on the promoter of its
target genes to induce cell proliferation. Aromatase inhibitors prevent the aromatase–dependent conversion of androgens to estrogens, whereas fulvestrant and
tamoxifen are both anti–estrogens that counteract the effects of estrogen by directly binding to the ER. CDK4 and CDK6 form complexes with CyclinD1 to stimulate
proliferation. Palbociclib, ribociclib, and abemaciclib are CDK4/6 small molecule inhibitors. CDK 4/6, cyclin–dependent kinases 4/6; DM1, derivative of maytansine 1;
Dxd, deruxtecan; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERK, extracellular–signal regulated kinase; HER2, human epidermal growth factor
2; HER3, human epidermal growth factor 3; MEK, mitogen–activated protein kinase kinase; mTOR, mammalian target of rapamycin; PDK, phosphatidylinositol–
dependent kinase; PI3K, phosphoinositide 3–kinase; RAF, rapidly accelerated fibrosarcoma; RAS, RAS proto–oncogene.
Another possible explanation for cross-resistance among
subsequent HER2-targeted drugs is represented by the clonal
evolution under the selective pressure of treatments. In this case,
based on tumor heterogeneity, trastuzumab or other HER2targeting drugs preferentially eradicate HER2+ clonal
populations selecting the HER2-negative ones, that in turn
emerge and drive tumor progression (41, 42, 44).
Similar cross-resistance has been reported between other
HER2-targeting agents. Neratinib is an irreversible HER2 TKI
approved for adjuvant treatment of HER2+/estrogen receptorpositive (ER+) early BC following adjuvant-trastuzumab-based
therapy, and, in combination with capecitabine, for HER2+
metastatic BC patients who have received two or more prior
anti-HER2-based regimens in the metastatic setting.
Evidence from a pre-clinical model of neratinib-resistant BC
cell lines indicates cross-resistance to trastuzumab and lapatinib.
This cross-resistance is bi-directional, as lapatinib- and
47.3% of trastuzumab-treated patients and in 63.2% of trastuzumab
plus pertuzumab-treated ones (46). In concordance, reduced TDM1 efficacy has been described in HER2+ advanced BC patients
previously treated with dual HER2 blockade by trastuzumab plus
pertuzumab combination as compared to trastuzumab alone
(47–51). At the molecular level, a marked reduction of HER2
expression on cell membrane and HER2 nuclear translocation
have been shown to account for cross-resistance between
trastuzumab plus pertuzumab and T-DM1 (47). In agreement
with reduced expression of HER2 on trastuzumab plus
pertuzumab rather than its loss, T-Dxd showed a remarkable
improvement in progression-free survival (PFS) vs T-DM1 in
second-line treatment for previously treated BC patients
(preliminary results from DESTINY Breast 03 trial, The Asco
Post, posted 9/19/21). This striking result is probably due to the
unique linker-payload system of T-Dxd, that contributes to its
preclinical efficacy against tumors with low HER2 expression (52).
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trastuzumab-resistant cells are also cross-resistant to neratinib
(53). In agreement, in phase II studies, drug-naïve patients
responded better to neratinib than patients previously treated
with trastuzumab (54) or with lapatinib (55).
Although the incidence of HER2+ disease in patients with GC
is similar to that observed in patients with BC, the success rate
achieved in BC with several HER2-targeted therapies has not yet
been observed in GC. This might be explained by biological
differences among these tumor types, such as the pattern of
expression of HER2, or the higher degree of intratumoral
heterogeneity of HER2 expression in GC compared to BC (56).
Nevertheless, based on data from the ToGA trial, the
combination of chemotherapy plus trastuzumab represents the
standard of care for first-line treatment of HER2+ advanced GC
(57). By contrast, HER2-targeted ADCs explored in the secondline setting showed promising results; in January 2021, based on
the robust data from DESTINY-Gastric01 phase II trial, the U.S.
FDA approved T-Dxd ADC for patients with metastatic GC who
have received a prior trastuzumab-based regimen (58). Although
the introduction of T-Dxd has represented an important step
forward, the benefit in this setting was much higher in patients
with a HER2 score of 3+ on immunohistochemical analysis
(IHC), while a lower response rate was observed in patients
with a 2+ score with positive results on in situ hybridization (58%
vs 29%) (58, 59). It is worth noting that in this study the HER2
status was evaluated using archival tissue specimens and thus the
HER2 status immediately prior to T-Dxd administration had not
been investigated. Indeed, similarly to what has been described in
BC, loss of HER2 expression after trastuzumab treatment has
been reported in patients with HER2+ advanced GC (60–63).
Another mechanism of cross-resistance among HER-2
targeted therapies involves the emergence of the HER2 L755S
variant after therapy. L755S is an activating mutation of HER2
accounting for 60% of HER2 mutations found in metastatic BCs
(64). Recent studies have described the emergence of HER2
L755S under the pressure of lapatinib and trastuzumab that
results in cross-resistance to other single agents or combination
HER2-targeted therapy, both in the pre-clinical and patientderived models (65, 66). Similarly, no significant response to
trastuzumab has been observed in HER2+ metastatic BC patients
whose tumors harbor HER2 mutations (67). In supporting the
association of HER2 mutations with trastuzumab resistance, the
frequency of acquired HER2 mutations in patients with advanced
BC after trastuzumab treatment is much higher compared to
patients with early-stage tumors, and an enrichment of HER2
mutations in metastatic lesions from patients undergoing
adjuvant trastuzumab has been reported (64, 68).
HER2 mutations account for cross-resistance also in HER2
non-amplified BC patients. In BC patients, about 70% of HER2
mutations have been found in metastatic ER+/HER2 nonamplified tumors, suggesting that the emergence of HER2
mutations may represent a mechanism of acquired resistance
to endocrine therapy (69). In line with this, Nayar and colleagues
described the appearance of HER2 mutations in metastatic
lesions from eight ER+ BC patients under the selective
pressure of ER-directed aromatase inhibitors, tamoxifen, or
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fulvestrant. An in vitro analysis showed that HER2 mutations
confer estrogen independence and resistance to tamoxifen,
fulvestrant, and to the Cycline Dependent Kinase 4 (CDK4)/
Cycline Dependent Kinase 6 (CDK6) inhibitor palbociclib, which
was overcome by combining ER-therapy with the HER2inhibitor neratinib (70). Overall, these data indicate that
acquired HER2 mutations account for cross resistance in i)
HER2+ BC patients treated with HER2-targeting agents, where
they are potentially useful biomarkers of trastuzumab/lapatinib
resistance in subsequent lines of treatments; ii) HER2- BC
patients treated with endocrine therapy.
Table 1 summarizes the cross-resistance events described
between sequential HER2-targeted therapies and ER-targeted
therapies and between ER-targeted agents and the CDK4/
CDK6 inhibitor Palbociclib.
CD4/6 Inhibitors
The clinical management of ER+ BC (mainly Luminal A and
Luminal B) includes endocrine therapy (ER downregulators,
selective ER modulators, and aromatase inhibitors) as primary
treatment, albeit luminal B tumors are mainly treated with
chemotherapy due to lower sensitivity to endocrine therapy
(71). However, resistance to endocrine therapy has been shown
to be dependent on the Cyclin D-CDK4/6 pathway (72). On this
basis, three CDK4/6 inhibitors, namely palbociclib (73),
ribociclib (74), and abemaciclib (75) have been FDA approved
in combination with endocrine therapy for the first- or secondline treatment of ER+ HER2- advanced BC (Figure 2). In an in
vitro model of ER+ HER2- BC cell lines, cross-resistance among
different CDKis has been reported, but not between CDK
inhibition and chemotherapeutic agents (76) (Table 2). Loss or
dysregulation of Retinoblastoma-associated Protein 1 (RB1) have
been demonstrated to emerge under selective pressure from
CDK4/6 inhibitors potentially conferring therapeutic resistance
(77, 78). Whether continuing a CDK4/6 inhibitor beyond
progression may prove to be an effective strategy is currently
being tested by several ongoing phase I and II trials (MAINTAIN
NCT02632045, PACE NCT03147287, NCT01857193, NCT
02871791, and TRINITI-1 NCT 02732119).
Recently, clinical cross-resistance mediated by PTEN loss has
been shown between CDK4/6 inhibitors and alpelisib, an alphaspecific PI3K inhibitor (PI3Ki) recently approved for the
treatment of PIK3CA-mutated ER+ advanced BC that
progressed on previous endocrine therapy (79, 80) (Table 2).
Costa and colleagues demonstrated that loss of Phosphatase and
Tensin Homolog (PTEN) promotes translocation of p27 outside
the nucleus by raising AKT activity, which in turn increases
CDK4/6 activity, ultimately overcoming the blockade of CDK4/6.
PTEN loss had been shown to cause resistance to
PhosphatidylInositol 3-Kinase (PI3K) inhibition in previous
studies (81, 82).
EGFR-Targeted Therapies
EGFR overexpression has been reported in diverse tumor types
including head and neck, ovarian and cervical cancers, Bladder
Cancer and CRC, where it has been associated with poor
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Subsequent
agent
T–DM1
Trastuzumab
Lapatinib
Trastuzumab
Tamoxifen
Fulvestrant
Palcociclib
Previous agent
Trastuzumab
+pertuzumab
Neratinib
Frontiers in Oncology | www.frontiersin.org
Lapatinib
Aromatase
inhibitors
Tamoxifen
Fulvestrant
Nayar U,
Nat genetics 2019 (70)
Cocco E,
Sci Signal 2018 (66)
Breslin S,
British J Cancer 2017 (53)
Bon G,
J Exp Clin Cancer Res 2020
(47)
Vici, Oncotarget 2017 (48)
Noda–Narita S, Breast Cancer
2019 (50)
Pizzuti L, Ther Adv Med Oncol
2021 (51)
Ref.
TABLE 1 | Cross–resistance in HER2– and ER–targeted therapies.
In vitro HER2–mutated
T47D and MCF7 BC
cell model + patient analysis
In vitro BT474 and
SkBr3 BC resistant cell
model + patient analysis
In vitro cell model
Observational
Observational
Observational
In vitro BT474 and SkBr3 BC resistant cell
model + Observational
Type of study
Emergence of HER2 L755S,
V777L, L869A, and S653C mutation
Emergence of HER2 L755S
mutation bidirectional
Increased cytochrome CYP3A4 activity
bidirectional
Reduction of membrane HER2 expression;
HER2 nuclear translocation
Proposed mechanism
Zuo WJ, Clin. Cancer Res 2016 (64)
Xu X, Clin Cancer Res 2017 (65)
Boulbes DR, Mol Oncol 2015 (67)
Yi Z, Breast Cancer 2020 (68)
Croessmann S, Clin Cancer Res 2019 (69)
Burstein HJ, J Clin Oncol 2003 (36)
Pectasides D, Anticancer Res 2006 (37)
Hurley J, J Clin Oncol 2006 (38)
Harris LN, Clin Cancer Res 2007 (39)
van de Ven S, Cancer Treat Rev 2011 (40)
Niikura N, Ann Oncol 2016 (41)
Mittendorf EA, Clin Cancer Res 2009 (43)
Gahlaut R, Eur J Cancer 2016 (45)
Ignatov T, Breast Cancer Res and Treat 2019 (46)
Pietrantonio F, Int J Cancer 2016 (60)
Saeki H, Eur J Cancer 2018 (61)
Seo S, Gastric Cancer 2019 (62)
Kijima T, Anticancer Res 2020 (63)
Burstein HJ, J Clin Oncol 2010 (54)
Awada A, Ann Oncol (55)
Supporting literature
Loria et al.
Cross-Resistance in Cancer Therapy
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TABLE 2 | Cross–resistance in CDK4/6–targeted therapies.
Previous
agent
Subsequent
agent
Ref.
Type of study
Palbociclib Abemaciclib
Ogata R,
Breast Cancer 2021 (70)
In vitro MCF7 and KPL4 BC
resistant cell model
Ribociclib
Costa C,
Cancer Discov 2020 (72)
Patient analysis +
CRISPR PTEN KO T47D
and MCF7 BC cell and
mouse model
Alpelisib
Proposed mechanism
Supporting literature
Downregulated retinoblastoma protein RB.
Hypothethical
Condorelli R, Ann Oncol.
2018 (71)
Pandey K, Int J Cancer 2019
(78)
Loss of PTEN, that results in p27 exclusion from Razavi P, Nat Cancer 2020
the nucleus and increased activation of CDK2
(73)
and CDK4
Juric D, Nature 2015 (74)
Concomitantly with the introduction of osimertinib in the
clinical practice, cross-resistance has been reported between
gefitinib and irreversible EGFR-TKIs in human lung cancer
cells (89). (Table 3) Mechanistically, in a gefitinib-resistant cell
model, Kelch Like ECH Associated Protein 1 (KEAP1) gene
mutation disrupts the KEAP1-Nuclear factor erythroid 2Related Factor 2 (NRF2) oncogenic signaling pathway leading
to constitutive activation of NRF2, cell proliferation, and
resistance to gefitinib as well as cross-resistance to afatinib and
osimertinib. Somatic mutations in the NFE2L2 (encoding NRF2)
and KEAP1 genes have been described in 23% of patients with
lung adenocarcinoma (LAC) (84) and are usually mutually
exclusive. Mutations in the KEAP1-NRF2 pathway have been
associated with worse clinical outcomes and earlier disease
progression to chemotherapy in LAC patients (90). More
importantly, the emergence of KEAP1 loss/NRF2 activation
has been reported as a mechanism of acquired resistance to
outcomes and prognosis (83). Furthermore, driver EGFR
activating mutations are common in NSCLC (84) and occur in
3% of CRC (85). For these reasons EGFR became a popular
therapeutic target; both EGFR-targeted mAbs and TKIs
demonstrated efficacy in large phase III clinical trials and were
approved for treating lung, colorectal and head and neck cancers.
EGFR-specific first-generation (gefitinib and erlotinib) or
second-generation (afatinib and dacomitinib) TKIs were
developed for treatment of patients with metastatic, EGFRmutated NSCLC (86). Given that up to 60% of patients
progressing on TKIs acquire the secondary EGFR T790M
mutation (87), the third generation irreversible EGFR TKI
osimertinib was developed which demonstrated clinical activity
in T790M patients who had progressed on previous TKIs
(Figure 3). Recently, based on results from the FLAURA trial
showing OS benefit over first-generation TKIs, upfront use of
osimertinib became the standard of care (88).
FIGURE 3 | Mechanism of action of EGFR–targeted drugs. EGFR activates Ras/Raf/MEK/ERK, PI3K/Akt/mTOR, and JACK1/2/STAT3 oncogenic signaling
pathways to stimulate growth and proliferation. Cetuximab and Panitumumab are mAbs that specifically inhibit EGFR. First–generation reversible (gefitinib and
erlotinib) and second–generation irreversible (afatinib and dacomitinib) TKIs were developed to target mutant EGFR. The third generation irreversible TKI Osimertinib
is highly selective for EGFR– activating mutations as well as the EGFR T790M mutation. EGF, epidermal growth factor; JACK1/2, janus kinases 1/2; STAT3, signal
transducer and activator of transcription 3; TGF–a, transforming growth factor alpha.
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TABLE 3 | Cross–resistance in EGFR–targeted therapies.
Previous
agent
Subsequent
agent
Ref.
Type of study
Gefitinib
Afatinib
Osimertinib
Park SH, FASEB J. 2018
(89)
In vitro HCC827 NSCLC resistant
cell model + In vivo resistant–
NSCLC mouse model
Cetuximab
Panitumumab Arena S, Clin Cancer Res.
2015 (98)
In vitro CRC resistant cell model
and EGFR–mutated CRC cell
model + patient analysis
Cetuximab
Cetuximab
Diaz LA Jr, Nature 2012
Panitumumab Panitumumab (102)
Misale S, Nature 2012
(103)
Van Cutsem E, J Clin
Oncol 2011 (104)
Patients’ sera analysis
In vitro DiFi and Lim1215 CRC
resistant cell model+
patient analysis
Phase III clinical trial
Supporting literature
KEAP1 mutation leading to
Krall EB, Elife 2017 (91)
constitutive activation of NRF2 Yamadori T, Oncogene 2012 (92)
Yu HA, Clin Cancer Res 2018 (93)
Hellyer JA, Lung Cancer 2019 (94)
Foggetti G, Cancer Discov 2021 (95)
Emergence of EGFR S464L,
Van Emburgh BO, Nat Commun 2016
G465R, and I491M mutations (99)
Misale S, Cancer Discov 2014 (100)
Montagut C, Nature Med 2012 (101)
Emergence of KRAS
Peeters M, Eur J Cancer 2015 (105)
mutations, indirect evidence.
De Roock W, Lancet Oncol 2015
Presumably bidirectional
(106)
Androgen Receptor-Targeted Therapies
EGFR-TKIs in EGFR-mutated LAC cells (91, 92) and patients
(93). Furthermore, patients with KEAP1-NFE2L2-mutant
tumors have shorter recurrence-free interval on treatment with
EGFR TKI (94) and KEAP1 inactivation reduces the sensitivity
of EGFR-driven tumors to osimertinib in an EGFR-driven
Trp53-deficient LAC mouse model (95). Overall, these results
suggest the involvement of KEAP1-NFE2L2 genetic alterations in
cross-resistance occurring between first-generation and thirdgeneration irreversible EGFR TKIs, that has been shown to be
overcome with the introduction of osimertinib as first-line
treatment. The post-osimertinib treatment options for EGFRmutated NSCLC including innovative drugs or combination
therapies are under investigation in ongoing clinical trials (96).
Cetuximab and panitumumab EGFR-targeted mAbs have
been approved in combination with chemotherapy for the
first-line treatment of Kirsten RAt Sarcoma (KRAS) wt CRC
(Figure 3). They can also be administered as monotherapy upon
progression following prior chemotherapeutic regimens. Despite
clinical benefits obtained in CRC by combining EGFR-targeted
mAbs and chemotherapy, this has been shown to last 8-10
months due to drug resistance (97). Multiple EGFR and RAS
mutations were among the mechanisms of resistance reported
(98, 99). EGFR acquired mutations preferentially occur in the
extracellular domain, which impair antibody-binding (100).
Among the different specific mutations identified in
cetuximab-resistant CRC patients, some proved to be
permissive for panitumumab binding, whereas others
determined cross-resistance (98, 101). The emergence of RAS
mutations induced by anti-EGFR therapies has been reported in
approximately 50% of patients with RASwt CRC and is
responsible for acquired resistance to cetuximab (102, 103)
(Table 3). RAS mutations can result in constitutive activation
of RAS-associated signaling that renders anti-EGFR therapies
ineffective for CRC. Consistent with this, the predictive role of
RAS mutations in the clinical responses of CRC to anti-EGFR
therapies has been demonstrated in several pivotal studies
(104, 106).
Frontiers in Oncology | www.frontiersin.org
Proposed mechanism
Prostate cancer (PC) is the most common cancer in men and is
dependent on the Androgen Receptor (AR) signaling for its
growth and progression (107). For this reason, androgen
deprivation represents the gold standard first-line treatment
for PC patients. Progression is due to transition from a
hormone sensitive stage to castration resistant disease (CRPC)
(108). Over the past decade, multiple treatment options have
demonstrated clinical efficacy in metastatic hormone sensitive
PC (mHSPC), non-metastatic CRPC (nmCRPC) and metastatic
CRPC (mCRPC) (109). The development of novel, highly potent
AR signaling inhibitors (ARSIs) such as enzalutamide and
abiraterone acetate (FDA approved in 2012, and 2018
respectively) (Figure 4) has represented a major step towards
more efficient inhibition of AR signaling and conferred survival
benefit in mCRPC and nmCRPC patients (110). Taxanes
represent the other class of current treatments for CRPC.
More recently, ARSIs have also been approved in hormonesensitive disease (111–113). With the adoption of ARSIs in early
disease, cross-resistance to sequential ARSI treatment has rapidly
emerged as a limitation in the sequential use of AR-targeted
therapies (110), however the optimal sequence of available ARSIs
and taxane-based chemotherapy have not yet been defined (114).
Data from pre-clinical models of abiraterone acetate- and
enzalutamide-resistant CRPC confirmed cross-resistance
among ARSIs (115, 116) and showed cross-resistance between
ARSIs and docetaxel but not carbazitaxel (117, 118) (Table 4).
Mechanistically, cross-resistance among enzalutamide and
abiraterone acetate is mainly caused by the re-activation of AR
pathway by the emergence of AR constitutively active splice
variants. Zhao and colleagues demonstrated the involvement of
the AR splice-variant 7 (AR-V7) and identified a Aldo-Keto
Reductase family 1 member C3 (AKR1C3)/AR-V7 axis, in which
AKR1C3 plays a dual function: first, it catalyzes androgen
synthesis; second, it binds AR-V7 promoting its stabilization
(116, 119). These data indicate that the AKR1C3/AR-V7 axis
plays critical roles in cross-resistance between enzalutamide and
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FIGURE 4 | Mechanism of action of AR–targeted drugs. AR is a transcription factor that is activated by androgenic hormones binding. Upon activation, AR
translocates into the nucleus where it activates the transcription of genes involved in cancer development and progression. Abiraterone acetate inhibits CYP17, the
enzyme responsible for the conversion of testosterone to dihydrotestosterone. Enzalutamide is a potent, competitive binder of androgens at the AR. It prevents the
translocation of the AR from the cytoplasm to the nucleus. AR, androgen receptor; CYP17, 17 a–hydroxilase/C17,20–lyase; PSA, prostate–specific antigen.
TABLE 4 | Cross–resistance in AR–targeted therapies.
Previous
agent
Subsequent
agent
Enzalutamide Abiraterone
Enzalutamide Apalutamide
Abiraterone
Darolutamide
Enzalutamide Docetaxel
Ref.
Type of study
Proposed mechanism
Lombard AP,
Mol Cancer Ther
2018 (115)
Zhao J,
Mol Cancer Ther
2020 (116)
In vitro CRPC resistant cell
model
In vitro CRPC resistant cell
model
Emergence of constitutively active AR
variants
Bidirectional
Activation of the axis AKR1C3/AR–V7
constitutively active variant
van Soest RJ,
Eur J Cancer 2013
(117)
In vitro PC346C resistant and
HEP3B PC cell model
Overlapping mechanism of action
(inhibition of AR nuclear translocation)
Liu C, Mol Cancer Ther 2019 (119)
Antonarakis ES, J Clin Oncol 2017
(121)
Guo Z, Cancer Res 2009 (123)
Azad AA, Clin Cancer Res 2015
(124)
Joseph JD, Cancer Discov 2013
(125)
Antonarakis ES, N Engl J Med 2014
(129)
Mezynski J, Ann Oncol 2012 (126)
Schweizer MT, Eur Urol 2014 (127)
van Soest RJ Eur. Urol 2015 (128)
The efficacy of chemotherapy after ARSIs treatment has been
investigated in multiple retrospective studies. Overall, clinical
evidence showed reduced efficacy of docetaxel in CRPC patients
previously treated with enzalutamide or abiraterone acetate (126,
127). Mechanistically, inhibition of AR nuclear translocation may be
implicated in cross-resistance as a common mechanism of action of
AR-targeting agents and docetaxel (117). Conversely, cabazitaxel
efficacy is not affected by prior ARSIs treatment (128).
Moreover, based on clinical evidence, it is widely recognized
that enzalutamide administration after abiraterone acetate is of
abiraterone acetate. In addition, patients treated with
enzalutamide or abiraterone acetate showed inferior OS and
PFS if they were AR-V7 positive rather than AR-V7 negative
(120, 121). On the other hand, AR splice variants do not affect
sensitivity to chemotherapy: similar overall survival (OS) and
PFS were observed in AR-V7 positive and negative patients
receiving taxanes (122). Accordingly, AR alterations including
gene aberrations and constitutively active splice variants arising
from prolonged ARSIs treatment have been widely implicated in
the development of resistance to ARSIs (110, 116, 120, 123–125).
Frontiers in Oncology | www.frontiersin.org
Supporting literature
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More recently, immunotherapies with checkpoint blockade
Abs directed against PD-1 and cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) have revolutionized the
treatment of patients with metastatic cancer including
melanoma (139) (Figure 5). Even though the optimal sequence
of targeted therapy and immunotherapy for the treatment of
patients with BRAF-mutated melanoma is still under
investigation in clinical trials [DREAMseq (NCT02224781) and
SECOMBIT (NCT02631447)], currently the American Society of
Clinical Oncology and the European Society of Medical Oncology
guidelines recommend both therapies as first-line treatment for
metastatic melanoma (140, 141). Due to the lack of mechanistic
knowledge indicating the best first-line therapy to adopt, many
centers treat these patients with targeted therapy first, and then
switch them to immunotherapy on progression. However, patients
who relapse on MAPK inhibition show a lower overall response
rate (ORR) to immunotherapy compared with MAPKi naïve
patients (142–144). In line with this, melanomas with acquired
resistance to MAPK inhibitors show CD8 T-cell deficiency/
exhaustion and loss of antigen presentation functions, which
suggests cross-resistance to anti-PD1/Programmed DeathLigand 1 (PD-L1) immunotherapy (145–147). More recently, a
cancer cell-instructed, immunosuppressive tumor
microenvironment lacking functional CD103+ dendritic cells
that preclude an effective T cell response has been described in
melanoma patients and mouse models (148). This mechanism is
involved in the cross-resistance between MAPK inhibitors and
subsequent immunotherapies (Tables 4, 5). Mechanistically,
greater clinical benefit than vice versa (129, 130), whereas the
CARD trial showed that switching to taxane chemotherapy is
preferred after ARSI failure (130).
MAPK Inhibitors
Genetic alterations affecting the RAS-RAF-MEK-ERK (MitogenActivated Protein Kinase, MAPK) pathway occur in
approximately 40% of all human cancers. Mutations in the
proto-oncogene BRAF and RAS family genes (KRAS and
NRAS) are quite frequent in melanoma, CRC, anaplastic
thyroid cancer (ATC) and LAC, whilst alterations affecting
genes encoding MEK and ERK have rarely been identified
(131, 132). For these reasons, targeting of the aberrantly
activated MAPK pathway is one of the most explored
therapeutic approaches in cancer. Among different neoplasms,
melanoma mostly benefited from MAPK-targeted therapy.
However, despite the survival advantages observed with BRAFtargeted drugs versus chemotherapy, many melanoma patients
progressed within 6-7 months (133, 134), mainly due to ERK reactivation (135). Based on clinical evidence from large clinical
trials (136–138), the current therapeutic strategy combines BRAF
and MEK inhibition, including three FDA approved
combinations for the treatment of metastatic BRAF-mut
melanoma: dabrafenib plus trametinib, vemurafenib plus
cobimetinib, and encorafenib plus binimetinib (Figure 5).
Moreover, dabrafenib plus trametinib combination has been
approved for the treatment of metastatic BRAF-mutated
NSCLC and metastatic/unresectable BRAF-mutated ATC.
FIGURE 5 | Mechanism of action of MAPK–targeted drugs and immunotherapies. The Ras/Raf/MEK/ERK signaling pathway is activated by several upstream
receptor tyrosine kinases. Dabrafenib, vemurafenib and encorafenib are specific BRAF–inhibitors used in the treatment of BRAF–mutant melanoma. In a strategy to
vertically target the MAPK signaling pathway, they are used in combination with trametinib, cobimetinib, and binimetinib respectively. Immune checkpoint blockade
inhibits the negative regulation of T cell activation, thereby unleashing antitumor T–cell responses. CTLA4, cytotoxic T–lymphocyte antigen 4; PD1, programmed cell
death protein 1; PDL–1, programmed death ligand 1; RTK, receptor tyrosine kinase.
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TABLE 5 | Cross–resistance in MAPK–targeted therapies.
Previous
agent
Subsequent
agent
Ref.
Dabrafenib
Dabrafenib
+trametinib
Anti–PD1
Anti–CTLA4
Haas L,
Nat Cancer 2021 (148)
Vemurafenib Dacarbazine
Dabrafenib
Radiotherapy
Vemurafenib
Type of study
Proposed mechanism
Supporting literature
RAFi and RAFi/MEKi
resistant melanoma
mouse model +
Patient analysis
Reprogramming of MAPK transcriptional
output driving immunosuppressive
microenvironment that lacks functional
CD103+ dendritic cells
Ackerman A, Cancer 2014 (142)
Johnson DB, J. Immunother 2017 (143)
Tet́ u P, Eur J Cancer 2018 (144)
Mason R, Pigment Cell Melanoma Res
2019 (145)
Hugo W, Cell 2015 (146)
Pieper N, Oncoimmunology 2018 (147)
Erdmann S,
Sci Rep 2019 (149)
Patient–derived resistant
melanoma cell model
Shannan B,
Eur J Cancer 2019
(151)
Patient–derived melanoma
cell model +
Observational
Reactivation of MAPK pathway and
enhanced activation of PI3K/AKT
signalling
Enrichment of H3K4 demethylase JAR–
ID1B/KDM5B, that regulates the
transcription of genes favoring cell survival
address this knowledge gap by providing a good deal of
information concerning specific drug scheduling.
RWD is referred to data collected from sources outside of
conventional research settings, including electronic health records,
administrative claims, tumor registries, daily clinical routine (153),
and information related to disease status, treatments and their
sequence, safety, concomitant medications, comorbidities, or to
cancer patient population not extensively enclosed in randomized
clinical trials (RCTs). As such, RWD is gaining increasing interest
for the potential to provide additional evidence that can
complement and support the data from RCTs.
RWD has significantly contributed to highlighting many
cross-resistance events. These include the reduction in T-DM1
activity observed in BC patients previously treated with dual
HER2 blockade by pertuzumab plus trastuzumab, as discussed in
detail above. Not only did observational studies in the real-world
setting (47–51) highlight cross-resistance but they also revealed
another critical issue: due to concomitant approval of
pertuzumab and T-DM1, none of the patients enrolled in the
EMILIA and Th3resa trials (T-DM1 registrative studies) had
previously received pertuzumab. Consequently, at the time of TDM1 approval, clinical data on its efficacy in pertuzumabpretreated patients was lacking.
Cross-resistance among ARSIs and between ARSIs and
taxane-based chemotherapy in PC have been extensively
addressed in this review. Recently, a systematic review (154)
has explored optimal treatment sequencing of abiraterone
acetate and enzalutamide in chemotherapy-naïve mCRPC
patients. The analysis was conducted with RWD from 17
observational studies and showed a favorable trend in
outcomes and cost effectiveness for the sequence abiraterone
acetate-enzalutamide compared to enzalutamide-abiraterone acetate.
In addition, RWD contributed in highlighting crossresistance between ARSIs enzalutamide and abiraterone acetate
(155) and suggested a reduced efficacy of sequential ARSI
treatment in chemotherapy pretreated patients.
Another relevant contribution deriving from RWD was the
demonstration of lower efficacy of immunotherapy in BRAFmutated metastatic melanoma patients relapsing on MAPK
inhibition compared with MAPKi naïve patients (144).
patients displaying MAPK re-activation who progress on dual
BRAF/MEKi, also exhibits an enhanced transcriptional output
driving immune evasion.
Another noteworthy cross-resistance event between unrelated
drugs that deserves mention, has been reported between the
BRAF inhibitor vemurafenib and dacarbazine chemotherapeutic
in a patient-derived BRAF-mutated melanoma cell model (149)
(Tables 4, 5). In this case, dacarbazine-resistant cells re-activate
the MAPK pathway by autocrine IL-8 cytokine, thereby
sustaining cross-resistance to vemurafenib. By contrast,
desensitization of vemurafenib-resistant cells to dacarbazine is
mediated by enhanced AKT serine/threonine kinase signaling.
Brain metastases affect approximately 50% of stage IV
melanoma patients requiring the combination of MAPK
inhibition or immunotherapy with radiotherapy protocols (150).
Cross-resistance between combined MAPK inhibition and
radiotherapy has also been observed (Tables 4, 5), but the
extent may vary depending on the treatment sequence (151).
Shannan and colleagues reported a higher rate of tumor relapse in
preclinical cell models that were first treated with BRAF inhibition
followed by radiotherapy compared to the reverse sequence. At the
molecular level, the histone H3K4 demethylase JARID1B/KDM5B
is more frequently upregulated following BRAF inhibition and
predicts cross-resistance towards radiotherapy.
REAL-WORLD DATA AS A TOOL TO
IDENTIFY CROSS-RESISTANCE
It is increasingly evident that, due to the recent rapid drug
development, pivotal clinical trials might not have explored the
full spectrum of the cancer population. A significant proportion
of cancer patients cannot be enrolled in clinical trials due to
stringent exclusion criteria, even though they are still treated in
clinical practice (152). Conversely, patients enrolled in clinical
trials exploring (for instance) a second-line treatment could not
have necessarily received current first-line treatments.
Consequently, there is an unmet medical need for additional
clinical practice information when choosing the optimal
sequence of new anticancer agents. RWD can potentially
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required patients to be re-tested for HER2 positivity before
being treated with T-Dxd.
The Darwinian selection hypothesis assumes that cancer
therapy selects pre-existing mutant cells that overtake the bulk
cell population. However, this is a simplified mechanism that
does not account for therapy resistance alone. In a more
complicated scenario, genetic alterations and changes in the
gene expression state often emerge under the selective pressure
exerted by the therapy itself, fueling the increasingly aggressive
behavior of recurring tumors (162).
On this basis, a molecular re-evaluation of patient recurrences
is of paramount importance in order to identify subsets of
patients to be included in RCTs where unfortunately re-biopsy
is not feasible in most cases. Recently, minimally invasive liquid
biopsy for the selection of patients for targeted therapies has
demonstrated equivalent clinical utility to that of invasive tumor
tissue testing (163). The analyses of cell-free tumor DNA
(ctDNA) allows a much more rapid identification of actionable
mutations compared to tissue profiling. Specifically, the ctDNA
analysis has been exploited to show the acquisition of specific
mutations on emerging resistance to targeted therapy (164).
Currently, a few FDA diagnostic tests have been developed to
provide tumor mutation profiling on NSCLC, BC, and ovarian
cancer. These tests have been used to select patients for targeted
therapy in the advanced setting. At the moment, global efforts
aim to obtain standardized procedures for liquid biopsy tests in
order to allow their rapid implementation into clinical practice.
The future use of this high-potential tool will rapidly help match
patients for clinical trials as well as for proper clinical
decision-making.
Finally, the real-world experience in EGFR-mutated NSCLC
demonstrated that sequential afatinib and osimertinib was
beneficial in prolonging the chemotherapy-free interval in
patients with T790M acquired resistance (156).
One challenging and unresolved issue relates to patients
affected by advanced hepatocarcinoma (HCC). The first-line
treatment of these patients is represented by the combination
of anti-VEGF bevacizumb and anti-PD-L1 atezolizumab mAbs,
that showed significant OS benefit over the multikinase inhibitor
(MKI) sorafenib previously used in this setting, which was
thereby approved by the FDA in 2020 (157). Data on efficacy
and safety were subsequently confirmed by RWD analyses (158).
Many therapeutic options are available for the second-line
treatment of these patients, including a MKI, mAbs, or antiPD1 agents such as cabozantinib, ramucirumab, nivolumab with
or without the anti-CTLA4 ipilimumab (159). At present, the
optimal second-line treatment has not yet been defined. An
observational retrospective study reported comparable efficacy of
second-line sorafenib and lenvatinib (160). Data from the realworld setting could help define the optimal sequence
of treatments.
STRATEGIES TO OVERCOME
CROSS-RESISTANCE
Molecular Re-Evaluation of Recurrences
as a Strategy to Refine
Clinical Trials Design
The loss of target on HER2-targeted therapy is a widely
recognized issue that has been discussed above for both BC
(36–47) and GC (60–62). Provided that the knowledge of the
underlying mechanisms is of paramount relevance, this evidence
offers the opportunity to reconsider the strategies behind the
design of RCTs. Indeed, many of these studies investigate the
efficacy of new therapeutic approaches in metastatic/recurring
patients stratified based on the molecular features of primary
tumors. Interpreting the results generated from these trials could
lead to sub-optimal clinical decision-making.
An emblematic example of this is the failure of the
randomized phase II study WJOG7112G (T-ACT). The aim of
the study was to explore the efficacy of paclitaxel with or without
trastuzumab in 99 patients with HER2+ advanced GC who had
disease progression after first-line chemotherapy with
trastuzumab. Median PFS and OS were not significantly
different between the two groups. In this case, loss of HER2
has been reported as a possible explanation for failure. Indeed,
when HER2 status was re-evaluated in tumor biopsy specimens
from 16 patients following disease progression, HER2 loss was
observed in 11 patients (69%) (161).
In the specific case of HER2-targeted therapy, re-evaluating
the HER2 status at the time of disease progression would be
required (43). Supporting this, an ongoing phase II, open-label,
single arm trial aimed at evaluating the efficacy and safety of TDxd in Western GC patients progressed with a trastuzumabcontaining regimen (DESTINY-Gastric02, NCT04014075)
Frontiers in Oncology | www.frontiersin.org
Identification of Collateral Sensitivities
The emergence of evolutionary dynamics (165, 166) and
nongenetic reprogramming of TME (167) in therapy resistance
provide a field of action for possible subsequent therapy.
Interestingly, available pre-clinical and clinical evidence
indicate cases of collateral sensitivities that are novel,
exploiting vulnerabilities emerging concurrently with
therapy resistance.
In the current scenario where most patients are still treated
with traditional chemotherapy, several cases of collateral
sensitivities between chemotherapeutic agents have been
reported. Pre-clinical and clinical evidence suggest that
cisplatin resistance can result in sensitivity to paclitaxel, and
vice-versa (168, 169). Despite the underlying mechanism
remaining unknown, combining the two drugs has been
proven to be effective in lung, ovarian, skin, breast, and head
and neck tumors (170). Similarly, vinblastine-resistant cell lines
are sensitive to paclitaxel, and vice-versa (171). In this case, the
two drugs exert opposing mechanisms of action (vinblastine
destabilizes microtubles while paclitaxel stabilizes microtubles);
resistance can stem from stabilizing (vinblastine) or destabilizing
(paclitaxel) mutations in a- and b- tubulin.
In the context of targeted therapies, the first collateral
sensitivity network was provided by Dhawan and colleagues in
2017. In an attempt to characterize collateral sensitivities to
several TKIs in Anaplastic Lymphome Kinase (ALK)-positive
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NSCLC, they found that cell lines resistant to first-line TKIs are
often sensitized to the chemotherapeutic drugs etoposide and
pemetrexed (172). More recently, the same authors showed that
resistance to chemotherapy in Ewing’s sarcoma cell lines is
associated with sensitivity to the histone demethylase 1
inhibitor SP-2509 (173).
These findings have fueled further exploration in pre-clinical
models, consequently expanding our knowledge in this field.
Melanoma cells which developed resistance to MAPKi showed
enhanced susceptibility to platinum-based drugs such as cisplatin
and carboplatin, that is inversely correlated with the expression level
of the p53 family member TAp73. Mechanistically, low TAp73
expression level results in reduced efficacy of the nuclear excision
repair system and enhanced sensitivity towards platinum-based
cytostatic agents (174). Similarly, resistance to BRAF/MEK
inhibitors is associated with increased levels of reactive oxygen
species and enhanced efficacy of the histone deacetylase (HDAC)
inhibitor vorinostat in resistant cell and mouse models, as well as in
patients (175). Accordingly, a pilot study in patients demonstrated
that treating BRAF inhibitor-resistant melanoma patients with
HDAC inhibitors killed the drug-resistant cell population (175).
In EGFR-mutant LUAD cells, acquired resistance in response to
EGFR inhibitors requires Aurora Kinase A activity, and is therefore
associated with increased sensitivity to Aurora kinase
inhibitors (176).
In the context of BC, HER2 mutations, resulting in crossresistance between HER2-targeted therapies, are associated with
higher efficacy of some irreversible HER2 TKIs such as neratinib
and pyrotinib both in HER2-amplified (65, 66) and HER2 nonamplified (177, 178) BC. In a panel of 115 cancer cell lines, neratinib
was the most effective against HER2-mutant cell lines among HER2targeted TKIs (179). The phase II SUMMIT trial concluded that
neratinib in combination with fulvestrant is clinically active in
heavily pretreated HER2-mutant HR+ BC patients (180). Thus,
HER2 mutations might be predictor of benefit from Neratinib
TKi. By employing a cell-model and 3D ex vivo organotypic
culture model, Singh and colleagues showed that a high level of
the detoxifying enzyme Sulfotransferase Family 1A Member 1
(SULT1A1) confers resistance to Tamoxifen and collateral
sensitivity to the anticancer compounds with SULT1A1-dependent
activity RITA (Reactivation of p53 and Induction of Tumor Cell
Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1) (181).
In pancreatic ductal adenocarcinoma (PDAC) patient-derived
organoids, chemotherapy-induced vulnerabilities were investigated
that highlighted increased sensitivity to MEK inhibition, driven by
tumor plasticity in response to chemotherapy regimen
FOLFIRINOX (combination therapy with Folinic Acid,
fluorouracil, irinotecan, and oxaliplatin) (182). In this case,
therapeutic vulnerabilities were identified by unbiased drug
screening experiments and did not seem to be associated with a
specific genetic marker. This is a significant indication that
molecular deregulations alone may not account for collateral
sensitivities, and an additional functional layer is needed for
precision oncology. Similarly, some of these studies suggested the
involvement of rapidly changing gene expression regulations in the
response to drugs rather than providing specific mechanisms for
collateral sensitivities.
Frontiers in Oncology | www.frontiersin.org
On the other hand, it is worth considering that our current
knowledge of potentially therapeutically targetable dependencies is
still limited and recurrently mutated genes account for this burden
only partially (183). New emerging categories of cancer targets that
include cell-autonomous and tumor microenvironment (TME)mediated targets, are likely to result in the development of novel
targeted agents and thereby novel therapeutic options in the
near future.
In this scenario, identifying predictive biomarkers to stratify
patients who would likely benefit from cancer therapies is
currently an active field of investigation. In this regard, it is
expected that many categories of drug-induced deregulation may
be considered, spanning from genetic/epigenetic deregulations to
nonmutational, functional alterations.
Investigation of Rational MechanisticBased Cancer Treatment Regimens
One strategy used to overcome resistance to targeted therapies is
represented by combination therapy simultaneously blocking
parallel or alternative pathways activated in cancer cells.
However, due to the complexity of signaling networks, efficient
screening for effective targeted combination therapies is a
challenging issue, which is further complicated by the need to
address clinically relevant doses and dosing schedules that can
impact the emergence and evolution of resistance.
Mathematical modeling represents a reasonable tool for
testing clinically relevant drug combinations prior to
investment in clinical trials. Branching process models had
been used to study resistance to chemotherapy in tumor cell
populations as early as in the 1980s (184). Since then, other
groups exploited mathematical modeling to characterize drug
resistance and investigate potential effective schedules in order to
minimize the development of acquired resistance (185, 186).
More recently, a computational modeling platform and software
package have been developed for identifying optimum dosing for
combination treatments of oncogene-driven cancers (187).
In addition, refining doses and scheduling in combination
therapy is of paramount importance in order to reduce the
emergence of resistance and cross-resistance. Currently, some
rational combination strategies are under investigation which have
the potential to reach this goal, thereby improving cancer therapy.
One of these strategies is represented by multiple low-dose
treatment. So far, the vast majority of novel cancer drugs are
developed as single agent therapies and are delivered to patients at a
maximum tolerated dose. In case of drug combinations, it is generally
believed that each drug should be used according to the same criteria.
However, recent available evidence indicates that multiple low-dose
treatment can be effective: in EGFR-mutant lung cancer, vertical
targeting of EGFR signaling pathway with three or four drugs can be
effective even when the drugs are used at 20% of the single agent
concentration (188). Similarly, dual RAF/ERK low-dose was effective
in KRAS-mutant cancers (189). In the specific case of vertical targeting
of multiple nodes of a signaling pathway, the adoption of a low-dose
regimen reduces the selective pressure on these nodes and the eventual
emergence of resistance mutation.
Sequential drug treatment is conceptually based on the
induction of a major vulnerability by the first drug, that is
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may play a key role in cross–resistance, as HER2 downregulation
is associated with a shorter interval between the last HER2–
targeted agent administered and the time of HER2 assessment
(45). At the moment, we do not know whether a reversible loss of
HER2 may be induced by HER2–targeting agents and to what
extent the reversible (internalization/nuclear translocation) and
irreversible (clonal selection) loss of HER2 could impact the
efficacy of subsequent therapy.
Many cross–resistance events have been reported between
therapies that exert different modes of action. Highly
representative of current practice is the recent cross–resistance
reported between dual BRAF/MEK inhibition and subsequent
immunotherapies. One fundamental point with this finding is
the acquisition of cross–resistance during MAPKi treatment,
questioning once again the hypothesis of clonal selection of
resistant cells pre–existing before therapy.
It is critical to decipher the underlying mechanism(s) of
cross–resistance in order to overcome it. To this aim, a
powerful tool is represented by recent studies that exploit
complex preclinical cell models including not only primary
tumor cells, but also cells from fibroblastic, vascular, and
immune compartments. These models resemble the tumor
heterogeneity and the contribution of TME and immune
compartments to cross–resistance dynamics which are typically
observed in vivo (198, 199) and therefore represent an ideal tool
for investigating new vulnerabilities.
Accordingly, the conceptual design behind RCTs needs to
swiftly and adequately incorporate the growing knowledge of
cancer evolution in response to therapy. Experience from
past RCTs indicates an urgent need to reconsider the
molecular landscape of recurring tumors and exploit newly
acquired targetable vulnerabilities for making more effective
therapeutic decisions.
targeted by a second drug to kill tumor cells. According to this
principle, sequential, but not simultaneous, treatment of triplenegative BC cells with EGFR inhibitors and DNA-damaging
drugs results in efficient cell killing (190). In metastatic BC
patients, pretreatment with cisplatin and doxorubicin resulted
in enhanced responses to anti PD-1 therapy (191). Also,
sequential drug treatment for combination immunotherapies is
supported by preclinical data (192).
Parallel to studies of drug scheduling, drug holidays, or
metronomic therapy, has also been proposed as a strategy to
limit the development of resistance in cancer treatment (193,
194). It is conceptually based on the principle that upon removal
of therapy, cancer cells do not need to develop advantageous
adaptations that drive resistance. From a molecular point of
view, this effect can be achieved by reversible adaptation (194) or
mutation–independent phenotypical variations (195). In
preclinical models of melanoma, intermittent dosing with
BRAF inhibitors results in delayed emergence of resistance as
compared to continuous dosing (196). However, conflicting
results derived from clinical data indicating that intermittent
dosing is inferior to continuous administration, highlighted that
careful attention must be paid when translating dosing and
treatment schedules from preclinical models to humans (197).
Overall, these efforts are intended to lay a solid mechanistic
basis for drug combination regimens and avoid clinical trials
investigating combination treatments without a rational basis.
CONCLUDING REMARKS
The emergence of drug resistance has proven to be a major obstacle
from the first available cancer chemotherapies available right up to
the latest, rapidly developing targeted therapies. Next–generation
sequencing and computational data analysis approaches have
revealed that genomic instability sustains tumor heterogeneity
which allows human cancers to escape from therapies and
develop resistance. An increasing number of therapeutic
possibilities available entails further levels of complexity and
cross–resistance to secondary or subsequent therapies can occur,
impacting on patient outcomes and survival rates.
The emergence of cross–resistance among drugs acting on a
shared target may occur. In response to the first specific agent,
threatened cancer cells acquire deregulation or mutation to the
target guaranteeing not only escape from therapy, but also cross–
resistance to a secondary drug acting on the same target. The
reversible/irreversible nature of target deregulation deserves
further investigation. It has been reported that the time
interval between consecutive HER2–targeted therapies in BC
AUTHOR CONTRIBUTIONS
GB, RL, PV, and FL were involved in manuscript drafting. GB,
SS, and MM–S revised the manuscript. All authors contributed
to the article and approved the submitted version.
FUNDING
This work was supported by Funds Ricerca Corrente 2022 from
Italian Ministry of Health.
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