Journal Article

Therapy-induced APOBEC3A drives evolution of persistent cancer cells

Benes, Cyril, Isozaki, Hideko, Langenbucher, Adam, Nikpour, Naveed, Archibald, Hannah L., Bilton, Samantha, Cabanos, Heidie Frisco, Phan, Nicole, Cobb, Rosemary G., Banwait, Mandeep Kaur, Hata, Aaron N., Zou, Lee, Engelman, Jeffrey A., Lin, Jessica J., Sequist, Lecia V., Gainor, Justin F., Oh, Sunwoo, Riley, Amanda, Lawrence, Michael S., Dyson, Nicholas J., Yeap, Beow Y., Lee, Jake June-Koo, Lawlor, Matthew, Timonina, Daria, Monroe, Susanna, Chan, Chang S., Buisson, Rémi, Abbasi, Ammal, Gomez-Caraballo, Maria, Su, Wenjia, Piotrowska, Zofia, Shaw, Alice T., Siddiqui, Faria M., Jalili, Pégah, Stanzione, Marcello, Maruvka, Yosef E., Sakhtemani, Ramin, Dionne, Kristin, Getz, Gad, Nangia, Varuna, Ott, Christopher J.

2023

Overview

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified 1 – 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. Induction of APOBEC3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that its suppression may represent a potential therapeutic strategy in the prevention of acquired resistance to lung cancer targeted therapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 38/15 / 38/23 / 38/39 / 38/91 / 42/89 / 45/77 / 631/67/1059/2326 / 631/67/1059/602 / 631/67/1612/1350 / 96/63 / 96/95 / Apolipoprotein B / Apolipoproteins / Bar codes / Biological evolution / Cloning / Cytidine deaminase / Cytidine Deaminase - deficiency / Cytidine Deaminase - drug effects / Cytidine Deaminase - genetics / Cytidine Deaminase - metabolism / DNA Breaks, Double-Stranded / DNA damage / Drug resistance / Drug Resistance, Neoplasm / Evolution / Gene deletion / Genomes / Genomic Instability / Humanities and Social Sciences / Humans / Lung cancer / Lung diseases / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Molecular modelling / Molecular Targeted Therapy / mRNA / multidisciplinary / Mutagenesis / Mutation / Patients / Polypeptides / RNA editing / Science / Science (multidisciplinary) / Therapy / Tumors