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binding site, is one commonly reported mechanism of mutant melanomas treated with small molecule RAF
resistance from an amino acid mutation or aberration. inhibitors, mutations in NRAS, MEK, and ERK, amplification
Amino acids may have different sizes, shapes, charges, and and alternative splicing of BRAF, and alternative regulation of
electrostatic properties which could directly change the ability MAP-3-kinases such as COT and C-RAF each have the
of the drug to interact with the target.74 One of the more potential to independently drive resistance by reactivating the
frequent mutations which impact the binding of a drug RAS−MAPK pathway.67 In terms of the activation of signaling
molecule is where a small amino acid is replaced by a larger pathways, examples include resistance to EGFR-targeted
amino acid, resulting in a steric clash and reduced binding monoclonal antibodies in metastatic colorectal cancer
affinity of the drug molecule. Alternatively, a polar amino acid (mCRC) through KRAS, BRAF, PIK3CA, or PTEN
side chain mutating to a hydrophobic amino acid or vice versa mutations.83 Additionally, it has been observed that activation
may break or disrupt polar interactions such as hydrogen of the phosphoinositide 3-kinase (PI3K)−AKT pathway
bonds.75 Resistance mutations often lead to single base or results in resistance to trastuzumab in the treatment of
amino acid substitutions, presumably reflecting the selection of HER2-amplified breast cancer.84 Examples of such pathway
the most commonly occurring variants by a natural selection alterations and how drug discovery scientists have considered
process. One well-established example of this is the T315I or addressed these are highlighted in selected case studies.
mutation of ABL in the treatment of patients with CML.76 Typical approaches to target resistance mechanisms through
This residue is known across protein kinases as the pathway alterations have been to identify novel drug molecules
“gatekeeper” due to its impact in the size and nature of of the newly activated pathway (or target), with the potential
groups which can bind in the adjacent “selectivity”, or “back” of combination treatments with agents inhibiting the original
pocket.77 In this example the “wild-type” residue is threonine, target.
which is small and hydrophilic, which is substituted for the 2.6. Apoptotic Defects
larger and more lipophilic isoleucine by the T315I mutation In 2002, Green and Evans proposed that deregulation of
resulting in a steric clash with targeted agents such as imatinib. proliferation, together with a reduction in apoptosis, creates a
The mutation of code for the gatekeeper residue in a protein platform that is both necessary and can be sufficient for
kinase is therefore one of the most frequent positions of cancer.85 Apoptosis defects are considered as a complement of
resistance also observed in EGFR, ALK, and ROS1 among protooncogene activation, as many deregulated oncoproteins,
many other kinases discussed in detail in later sections.78 such as MYC, which drive proliferation can also trigger
2.4.2. Impact on Cofactor Affinity. If the mechanism of apoptosis. The ultimate goal of most cancer drugs is to trigger
action (MOA) of a drug molecule is through competition with tumor-selective cell death. As part of this induction of
a cofactor (or substrate), then resistance can occur if the apoptotic-type of cell death in targeted cells, it is likely that
affinity of such a cofactor or substrate is increased. One of the disruption of the apoptotic machinery may impact resistance to
most well-characterized examples of this effect is from the anticancer drugs.86 In particular, resistance to chemotherapy
T790M gatekeeper mutation in EGFR on the activity of appears to be associated with such defects in the cell death
inhibitors such as gefitinib and erlotinib.79 When this mutation machinery, and it has been therefore postulated that targeting
was first identified, it was considered most likely to impact caspase-dependent and independent pathways may be required
through steric considerations, similarly to T315L in BCR/ABL. for optimal killing of tumor cells.87 There are molecular
However, it was later shown that a major impact of the T790M mechanisms that tumor cells use to suppress apoptosis such as
mutation was due to an increase in affinity of the kinase toward BCL-2 or downregulation or mutation of proapoptotic
adenosine triphosphate (ATP), thus rendering these drugs proteins such as BAX induces resistance to apoptosis.88 This
significantly less active in cellular experiments.80 This mutation mechanism is one of the limited number of apoptotic pathways
is observed in over 50% of patients treated with these drugs, currently targeted by FDA-approved medicines. Recent studies
which resulted in a clear unmet medical need. have defined a critical role for the antiapoptotic protein MCL-1
2.4.3. Conformational Change of Target. Consistent as a driver of adaptive resistance in tumor cells treated with a
with how nonsynonymous mutations can activate kinases range of targeted therapies, including those inhibiting BRAF
through conformational change, it is possible for mutants to and EGFR. Other opportunities may include the discovery of
cause resistance through such mechanisms. In the previously therapeutics to trigger the extrinsic apoptosis pathway or those
discussed drug target BCR/ABL, the L248V mutation has been which target tumor suppressor pathways and or the micro-
rationalized as causing resistance not only due to reduced environment. Finally, immune-checkpoint inhibition has been
steric complementary with imatinib, but additionally from a reported to induce apoptosis in cancer cells which may lead to
destabilization of the inactive conformation to which this “type the potential of combination approaches with both targeted
II” inhibitor binds to.81 This has also been postulated to be the medicines and chemotherapies.
case for reported “P-loop” mutations such as Y253C and
2.7. Phenotype Switching
E255K/V which also destabilize the inactive conformation of
the protein.78 Phenotype switching (also known as “cell plasticity”) is a
change between multiple cellular morphologies, which can act
2.5. Signaling Pathway Alterations
as a mechanism of resistance independent of the pathway
In some cases cancer cells can achieve resistance to treatment targeted by the drug. A recent review by Boumahdi and de
through adaptation driven by specific genetic alterations, which Sauvage presents a comprehensive description of cell plasticity
can result in the activation of signaling pathways that can as a mechanism of targeted therapy escape in various cancers.89
enable cancer cells to survive drug treatments.67,82 This could Such plasticity in tumor cells may enable transformations
involve the reactivation of the signaling pathway being targeted toward phenotypic states which no longer depend on the
or an alternative pathway activated to circumvent target pathway to which the drug is targeted. These pools of drug
inhibition. As an example of pathway reactivation, in BRAF refractory cells may have the ability to regain drug sensitivity
G https://dx.doi.org/10.1021/acs.chemrev.0c00383
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