Chemical Reviews pubs.acs.
org/CR Review
on treatment discontinuation or acquire permanent resistance combination of BRAF and PI3K inhibitors. In addition,
to therapy, contributing to the failure of therapy. Recently, cell mathematical modeling has been used to enable understanding
plasticity has emerged as potential resistance mechanisms to of whether specific drug resistance is driven by spontaneous or
targeted therapies across cancer types including melanoma, induced mutations.95 As a final example, Yates et al. recently
lung cancer, and basal cell carcinoma. Both transdifferentiation published their work to understand resistance mechanisms for
and epithelial−mesenchymal transition (EMT) are examples of the EGFR inhibitor AZD3759, which suggested the driver for
cell plasticity leading to drug resistance. As an example of such resistance was a small proportion of cells being resistant at
transdifferentiation, the phenotypic transformation of EGFR baseline.96
mutant lung adenocarcinoma (LUAD) into small cell lung 2.9. Evolution of Methodology for Detection of Mutations
cancer (SCLC) has been identified as a clinical mechanism of and Resistance in Clinical Practice
resistance to EGFR inhibitors. The transformation to SCLC at
the time of drug resistance is determined by histological The ability to accurately detect nonsynonymous mutations or
examination and expression of neuroendocrine markers. The signaling aberrations in patients can be critical to provide them
prognosis once SCLC has been diagnosed is poor, and current with the best treatment options. When drug resistance occurs
treatments used in the treatment of SCLC are ineffective. in cancer patients, disease progression can occur extremely
Importantly, tumors transformed to the SCLC state harbor the rapidly. However, the ability to detect when patients may be
original activating EGFR mutation, suggesting direct evolution about to become resistant and the mechanism of this resistance
from the initial cancer, rather than a distinct, second primary could be impactful in directing their subsequent treatment
cancer. A recent study showed that EGFR inhibitor-resistant options. Therefore, understanding the prevalent resistance
LUADs and SCLCs share a common clonal origin and undergo mechanisms from approved cancer drugs will enable drug
branched evolutionary trajectories. The clonal divergence of discovery scientists a clear rationale for how such resistance
SCLC ancestors from the LUAD cells occurred before the drug may be targeted. Next generation sequencing methods are now
treatments, and complete inactivation of both RB1 and TP53 routinely used as part of the diagnosis of cancer patients.97
were observed from early LUAD stages in tumors. This approach has truly revolutionized sequencing methods
Epithelial−mesenchymal transition (EMT) is a critical and enables the sequencing of millions of DNA fragments with
mechanism which enables tissue remodeling during the previous sequence knowledge across the exome. Such methods
morphogenesis of multicellular organisms.90 The causal are now in relatively common use for mutation detection at
relationship between EMT and cancer metastasis is yet to be diagnosis through approaches such as circulating tumor DNA
fully understood; however, the role of EMT in drug resistance (ctDNA), to monitor the emergence of additional resistance
is being recognized as an important emerging factor.91 A mechanisms or to predict the potential for a patient to respond
number of EMT-related signaling pathways have been reported to certain treatments through the use of validated bio-
as being important in the drug resistance of cancer cells, markers.98,99
including the silencing of tumor suppressors as innate and 2.9.1. Predicting Mechanisms of Clinical Resistance.
acquired mechanisms. Interestingly, cells undergoing EMT One way of enabling drug discovery scientists to target drug
have shown features most commonly observed in cancer stem resistant mutations more effectively would be to identify such
cells (CSCs).92 A novel emerging opportunity is to therefore putative resistance mechanisms as early as possible. Under-
combine the targeting of EMT with other targeted cancer standing the range of likely mechanisms of resistance with high
drugs or chemotherapies. levels of confidence for clinical drug candidates may enable
Significant progress is being made into understanding the additional drug discovery projects to be initiated ahead of
mechanisms of this phenotypic switching behavior and the role observing such resistance in a patient’s following treatment.100
in cancer drug resistance, including the role of reprogramming It may take many years for resistance mechanisms to be
factors and chromatin remodeling. Enabling further under- confirmed in a clinical setting, and increasing this rate of
standing of tumor cell plasticity on the molecular level may feedback and learning would enable more rapid generations of
enable new therapeutic strategies to be considered which, future drugs to be discovered. Alternatively, in early stages of
combined with existing treatments, may result in deeper and drug discovery where medicinal chemists are selecting
longer-lasting cancer treatments. preferred series, such information may inform if certain
chemical scaffolds are more vulnerable to putative resistance
2.8. Mathematical Modeling Approaches to Understand mechanisms than others.
Mechanisms of Resistance Drug resistance mechanisms are typically categorized as
Mathematical modeling approaches have proved valuable to either innate or preexisting. Innate resistance mechanisms are
assist drug discoverers in the understanding of the mechanism instances where the tumor does not respond to the drug; these
behind mechanisms of resistance.93 As every increasing data on tumors effectively have an in-built mechanism of resistance to
the emergence of resistance mechanisms has been disclosed, certain therapies.101 This could be explained by a number of
mathematical modeling and computational predictions (using generic factors such as the wrong patient population or
systematic and quantitative approaches) have become inadequate target engagement, although there may be more
increasingly important to provide deeper insights, generate target-specific explanations such as pathway feedback activa-
hypotheses, or potentially suggest promising treatment tion or alternative pathway activation. Preexisting mutations
strategies for future testing. may occur in very low levels and become more prevalent on
In one recent study, such a mathematical modeling approach drug treatment which may result in a patient initially
was used which connected potential underlying mechanisms of responding to a drug which is then followed by the emergence
resistance to patient survival data.94 Specifically, the model of resistance. Acquired resistance mutations, on the other
predicted that different patterns of synergy exist for the hand, may arise and be observed only under pressures of drug
combination of BRAF and MEK inhibitors than for the treatment and (similar to preexisting mutations) may become
H https://dx.doi.org/10.1021/acs.chemrev.0c00383
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