Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Hideko Isozaki (), Ramin Sakhtemani, Ammal Abbasi, Naveed Nikpour, Marcello Stanzione, Sunwoo Oh, Adam Langenbucher, Susanna Monroe, Wenjia Su, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L. Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Justin F. Gainor, Jessica J. Lin, Lecia V. Sequist, Zofia Piotrowska, Beow Y. Yeap, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef E. Maruvka, Rémi Buisson, Michael S. Lawrence () and Aaron N. Hata ()
Additional contact information
Hideko Isozaki: Massachusetts General Hospital Cancer Center
Ramin Sakhtemani: Massachusetts General Hospital Cancer Center
Ammal Abbasi: Massachusetts General Hospital Cancer Center
Naveed Nikpour: Massachusetts General Hospital Cancer Center
Marcello Stanzione: Massachusetts General Hospital Cancer Center
Sunwoo Oh: University of California Irvine
Adam Langenbucher: Massachusetts General Hospital Cancer Center
Susanna Monroe: Massachusetts General Hospital Cancer Center
Wenjia Su: Massachusetts General Hospital Cancer Center
Heidie Frisco Cabanos: Massachusetts General Hospital Cancer Center
Faria M. Siddiqui: Massachusetts General Hospital Cancer Center
Nicole Phan: Massachusetts General Hospital Cancer Center
Pégah Jalili: University of California Irvine
Daria Timonina: Massachusetts General Hospital Cancer Center
Samantha Bilton: Massachusetts General Hospital Cancer Center
Maria Gomez-Caraballo: Massachusetts General Hospital Cancer Center
Hannah L. Archibald: Massachusetts General Hospital Cancer Center
Varuna Nangia: Massachusetts General Hospital Cancer Center
Kristin Dionne: Massachusetts General Hospital Cancer Center
Amanda Riley: Massachusetts General Hospital Cancer Center
Matthew Lawlor: Massachusetts General Hospital Cancer Center
Mandeep Kaur Banwait: Massachusetts General Hospital Cancer Center
Rosemary G. Cobb: Massachusetts General Hospital Cancer Center
Lee Zou: Massachusetts General Hospital Cancer Center
Nicholas J. Dyson: Massachusetts General Hospital Cancer Center
Christopher J. Ott: Massachusetts General Hospital Cancer Center
Cyril Benes: Massachusetts General Hospital Cancer Center
Gad Getz: Massachusetts General Hospital Cancer Center
Chang S. Chan: Rutgers Robert Wood Johnson Medical School and Center for Systems and Computational Biology, Rutgers Cancer Institute
Alice T. Shaw: Massachusetts General Hospital Cancer Center
Justin F. Gainor: Massachusetts General Hospital Cancer Center
Jessica J. Lin: Massachusetts General Hospital Cancer Center
Lecia V. Sequist: Massachusetts General Hospital Cancer Center
Zofia Piotrowska: Massachusetts General Hospital Cancer Center
Beow Y. Yeap: Massachusetts General Hospital Cancer Center
Jeffrey A. Engelman: Massachusetts General Hospital Cancer Center
Jake June-Koo Lee: Massachusetts General Hospital and Harvard Medical School
Yosef E. Maruvka: Faculty of Biotechnology and Food Engineering, Lorey Loki Center for Life Science and Engineering, Technion
Rémi Buisson: University of California Irvine
Michael S. Lawrence: Massachusetts General Hospital Cancer Center
Aaron N. Hata: Massachusetts General Hospital Cancer Center

Nature, 2023, vol. 620, issue 7973, 393-401

Abstract: Abstract Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1–4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.

Date: 2023
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DOI: 10.1038/s41586-023-06303-1

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