Abstract IA09: Non-mutational resistance to anti-cancer drugs

“Rationally-targeted” oncology drugs can deliver significant therapeutic benefit in genomically-defined subsets of cancer patients. However, the clinical benefit associated with these agents is substantially limited by the nearly invariable emergence of drug resistance over time. In many cases, specific mutational mechanisms of resistance have been elucidated, presumably reflecting the clonal selection of stochastically-generated mutations that were present prior to treatment; however, additional pre-clinical and clinical findings implicate non-mutational mechanisms as well. We have identified and characterized a small subpopulation of reversibly “drug-tolerant” cells. The drug-tolerant phenotype is associated with a distinct chromatin state, and is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity. The drug-tolerant subpopulation can be selectively ablated by treatment with certain chromatin-modifying agents, potentially yielding a therapeutic opportunity. Furthermore, this subpopulation appears to contain the precursors of drug-resistant clones that acquire mutations during, rather than prior to, drug treatment. Additional studies of non-mutational drug resistance mechanisms implicate the rewiring of growth factor-responsive cellular signaling pathways as a common survival mechanism within tumor cell populations. These findings suggest that cancer cell populations employ various epigenetically-determined survival strategies to establish sufficient phenotypic variation among cells in order to protect the population from eradication by potentially lethal exposures. Citation Format: Jeff Settleman. Non-mutational resistance to anti-cancer drugs. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA09.