June 9, 2020

Christopher Bassil (Duke University)

Evolutionary trade-offs in drug-resistant cancers

Spring 2020 Graduate Student Award in Cancer and Evolution

Although modern cancer therapies produce encouraging clinical responses, these improvements are often only temporary. This is in part because cancer itself is an evolutionary disease: when faced with anti-cancer drugs, tumors simply evolve to acquire drug resistance. Once a tumor has developed drug resistance, the challenges in treating it are twofold: (1) drug-resistant tumors can evolve multiple different mechanisms to resist a drug; and, (2) any individual drug-resistant tumor will evolve many of these different mechanisms simultaneously. Thus, treatments which block some mechanisms are incomplete, and those which block them all are toxic and infeasible. New approaches to drug- resistant tumors are therefore needed. One idea is to exploit the evolutionary process responsible for the development of drug resistance itself. As tumors evolve drug resistance, they alter their biology to protect themselves from the specific anti-cancer drugs used to treat them. Although these changes benefit tumors, they also come with side effects: new, unexpected vulnerabilities which are specific only to drug-resistant cancers. We have discovered that these weaknesses, or “collateral sensitivities,” occur broadly in drug-resistant cancers. We have even uncovered specific collateral sensitivities which are shared across many different mechanisms of resistance. Instead of trying to block tumor strategies for drug resistance directly, then, we propose to treat these diseases by identifying their hidden weaknesses, and using them to undermine the development and progression of drug-resistant cancers. This proposal uses genome-wide CRISPR/Cas9 screening to systematically uncover and characterize collateral sensitivities in EGFR-inhibitor-resistant, EGFR-mutant non-small cell lung cancer.