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Mutations and Drug Resistance

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A drug must interact with its target(s) to achieve the therapeutic effects. Mutation in drug target is a critical mechanism that results in drug resistance. The aim of this topic is to highlight clinically-relevant mutations in drug targets that lead to resistance to anticancer or antivirus agents as well as ...

A drug must interact with its target(s) to achieve the therapeutic effects. Mutation in drug target is a critical mechanism that results in drug resistance. The aim of this topic is to highlight clinically-relevant mutations in drug targets that lead to resistance to anticancer or antivirus agents as well as current strategies in overcoming these resistances.

There are several scenarios under which a mutation could lead to drug resistance. Mutations could reduce the binding affinity of a drug to its target or render the target constitutively active. Worse yet, mutations could turn a drug from an antagonist into an agonist. For example, current therapeutic strategy for advanced prostate cancer is to inhibit the androgen receptor (AR) signaling. However, the W741C mutation in the AR was found to convert bicalutamide from an antagonist of the wild type AR into an agonist of the W741C AR mutant, which actually promotes tumor growth. What’s more, multiple resistant mutations in AR could be found in the same patients. Thus, one way to overcome drug resistance is to develop AR inhibitors that are active against multiple AR mutants. In another scenario, a mutation could cause disruption or aberrant interaction of a specific protein-protein interaction, resulting in drug resistance.

In general, resistant mutations in drug targets are derived from tissue specimen of the patients that are resistant to the drug. Next, mutation-related resistance is demonstrated in a series of in vitro and in vivo models. Novel drug candidates effective against the mutated targets in experimental models are developed, and their efficacy in patients bearing such resistant mutations is further demonstrated. We welcome review articles that cover one or more of these steps in the area of anticancer or antivirus agents.


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