Elucidate the landscape of druggable targets for eliminating cancer persister cells

PROJECT SUMMARY Residual disease, caused by incomplete killing of cancer cell populations, is a critical limitation of targeted therapy, and almost inevitability leads to tumor recurrence. A growing body of evidence suggests a significant contribution of persister cells to residual disease. Persister cells are small subpopulations of the original tumor that survive presumed lethal doses of targeted therapy via non-genetic mechanisms of drug tolerance. Eliminating persister populations before they have a chance to evolve genetic resistance mutations will improve the durability of targeted therapies. However, signals that promote and targets that eliminate persistence are poorly characterized. Our goal is to elucidate mechanisms of persister rewiring and pinpoint druggable targets to eradicate persistence in KRAS-mutant non-small cell lung cancer. Our aims are designed to: (Aim 1) illuminate signals that promote persistence in physiopathological contexts; (Aim 2) identify and validate targets that inhibit persistence; and (Aim 3) establish a persister knowledge base and AI-enabled tools to continuously generate target hypotheses. Elucidating pro-persistence signals and nominating preclinically validated drug targets will enable rational design of combination treatment strategies that limit opportunities for resistance to evolve with KRAS G12C drug-treated NSCLC.