Abstract IA019: Resolving the paradigm of the pre-existing resistance to targeted therapy, and the fitness costs associate with resistance: In vitro and theoretical evidence using an evolutionary game theoretic approach

Abstract

Abstract Therapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies attempt to delay resistance via judicious treatments that maintain a significant treatable subpopulation. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. To bridge this gap, we recently developed an in vitro assay to directly measure the parameters of the underlying evolutionary game played between cancer cells under therapy. Using this assay we have subsequently directly observed competitive exclusion in non-small cell lung cancer cells – a necessary, but not sufficient condition for adaptive therapy. Intrinsic to this finding lies another advance: one which helps us settle the long standing paradox of pre-existing resistance and fitness costs associated with resistance mutations. In particular, if a cost of resistance exists, how can a less fit mutant persist in a population long enough for a treatment to be given to expose its increased fitness? To answer this, we show experimental and theoretical results that help explain this paradox which we posit submit should be generalizable outside cancer and applicable across the kingdoms of life where eco-evolutionary dynamics are at play. Citation Format: Jacob G. Scott. Resolving the paradigm of the pre-existing resistance to targeted therapy, and the fitness costs associate with resistance: In vitro and theoretical evidence using an evolutionary game theoretic approach [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA019.