2020 Lung Cancer Research Foundation Annual Grant Program
Hideko Isozaki, PhD
Massachusetts General Hospital
Targeting APOBEC3A induction as a new therapeutic strategy to prevent acquired drug resistance in non-small cell lung cancer
The development of therapies that target oncogenic driver mutations has transformed the treatment of lung cancer. Despite notable progress in the design of successive generations of drugs with more potent activity and improved side-effect profiles, the inevitable development of acquired drug resistance continues to limit the clinical efficacy of these agents. Thus, there remains an urgent need for innovative therapeutic approaches to combat drug resistance. There is increasing evidence that given enough time, cancer cells that initially evade therapy can subsequently evolve new mechanisms of drug resistance. We recently discovered that residual lung cancer cells that have survived targeted therapy treatment exhibit activation of the APOBEC3A cytidine deaminase, a powerful mutator that can cause point mutations as well as DNA damage. Moreover, we found that genetic deletion of APOBEC3A suppresses the emergence of resistant cells during targeted therapy treatment. These results suggest that genomic instability caused by APOBEC3A may accelerate tumor evolution and facilitate drug resistance.
In this project, we will test the hypothesis that preventing APOBEC-driven evolution of cancer cells treated with targeted therapies will prevent the development of acquired drug resistance. Despite many attempts to develop inhibitors of APOBEC proteins, these enzymes remain undruggable. As an alternative approach, we propose to indirectly inhibit APOBEC3A mutagenesis by suppressing its expression. Using patient-derived models of EGFR, ALK and KRAS mutant lung cancer, we will determine the mechanistic basis for APOBEC3A induction and identify potential therapeutic targets for preventing the evolution of drug resistant cells during targeted therapy treatment. Successful completion of this study will provide scientific rationale for a new therapeutic approach designed to alter the evolutionary trajectory of cancer cells and prevent acquired drug resistance.