Abstract IA006: Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy

Abstract

Abstract Evolutionary dynamics underlie carcinogenesis, with tumor cells constantly adapting, resulting in cell populations that outgrow their non-tumor cell neighbors, evade treatment, and ultimately lead to death. Well-designed therapies to treating cancer induce immense and specific selection. The heterogenous cancer cell population either goes extinct or continues to evolve during and in response to the therapeutically induced bottleneck, leading to a subsequent selective sweep and newfound prominence of cells exhibiting the resistance phenotype. However, this bottleneck period provides a unique opportunity wherein the diversity of cells constituting the tumor is predictably reduced. Here, we introduce a framework to quantify the selection upon variants before, during, and after the therapeutic bottleneck, facilitating richer understanding of the mechanisms by which therapeutic resistance is acquired. We additionally couple measures of selection intensity with the prediction of neoantigens in a cohort of patients to identify potential orthogonal targets for immunotherapy. The result is a schema for leveraging predictability induced by the primary therapeutic bottleneck to drive the remnant tumor cell population to extinction. Finally, we demonstrate the utility of this schema in mutant EGFR lung adenocarcinoma. Citation Format: J. Nic Fisk, Katerina Politi, Scott Gettinger, Jeffrey P Townsend. Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA006.