No abstract

Evolved resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR T790M mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified FGFR1 as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data has not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug tolerant cells over long time periods, preventing the development Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Drug resistance is perhaps the greatest challenge in improving outcomes for cancer patients undergoing treatment with targeted therapies. It is becoming clear that “persisters,” a subpopulation of drug-tolerant cells found in cancer populations, play a critical role in the development of drug resistance. Persisters are able to maintain viability under therapy but are typically slow cycling or dormant. These cells do not harbor classic drug resistance driver alterations, and their partial resistance phenotype is transient and reversible upon removal of the drug. In the clinic, the persister state most closely corresponds to minimal residual disease from which relapse can occur if treatment is discontinued or if acquired drug resistance develops in response to continuous therapy. Thus, eliminating persister cells will be crucial to improve outcomes for cancer patients. Using lung cancer targeted therapies as a primary paradigm, this review will give an overview of the characteristics of drug-tolerant persister cells, mechanisms associated with drug tolerance, and potential therapeutic opportunities to target this persister cell population in tumors.