Abstract
Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.
Competing Interest Statement
The authors declare competing financial interests: A.N.H. has received grants/research support from Novartis, Amgen, Pfizer, Eli Lilly, Roche/Genentech, Eli Lilly, Relay Therapeutics and Blueprint Medicines. L.V.S. has served as a compensated consultant for Genentech, AstraZeneca and Janssen, and has has received institutional research support from BI, AZ, Novartis, Genentech, LOXO and Blueprint Medicines. Z.P. has served as a compensated consultant or received honoraria from C4 Therapuetics, Blueprint Medicines, Jazz Pharmaceuticals, Janssen, Medtronic, Eli Lilly, InCyte AstraZeneca, Genentech, Spectrum, Ariad/Takeda, Novartis, AbbVie and Guardant Health, and receives institutional research funding from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro and Cullinan Oncology. J.J.L. has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, Blueprint Medicines, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Roche/Genentech, Pfizer, and Novartis; and received travel support from Pfizer. C.B., A.T.S. and J.A.E are currently are currently employees of Novartis, Inc. (their contributions to the manuscript occurred while they were employees of Massachusetts General Hospital).