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Therapy-induced APOBEC3A drives evolution of persistent cancer cells.

Authors :
Isozaki H
Sakhtemani R
Abbasi A
Nikpour N
Stanzione M
Oh S
Langenbucher A
Monroe S
Su W
Cabanos HF
Siddiqui FM
Phan N
Jalili P
Timonina D
Bilton S
Gomez-Caraballo M
Archibald HL
Nangia V
Dionne K
Riley A
Lawlor M
Banwait MK
Cobb RG
Zou L
Dyson NJ
Ott CJ
Benes C
Getz G
Chan CS
Shaw AT
Gainor JF
Lin JJ
Sequist LV
Piotrowska Z
Yeap BY
Engelman JA
Lee JJ
Maruvka YE
Buisson R
Lawrence MS
Hata AN
Source :
Nature [Nature] 2023 Aug; Vol. 620 (7973), pp. 393-401. Date of Electronic Publication: 2023 Jul 05.
Publication Year :
2023

Abstract

Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified <superscript>1-4</superscript> , 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.<br /> (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Details

Language :
English
ISSN :
1476-4687
Volume :
620
Issue :
7973
Database :
MEDLINE
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
37407818
Full Text :
https://doi.org/10.1038/s41586-023-06303-1