Author:
Yazinski Stephanie A.,Comaills Valentine,Buisson Rémi,Genois Marie-Michelle,Nguyen Hai Dang,Ho Chu Kwen,Todorova Kwan Tanya,Morris Robert,Lauffer Sam,Nussenzweig André,Ramaswamy Sridhar,Benes Cyril H.,Haber Daniel A.,Maheswaran Shyamala,Birrer Michael J.,Zou Lee
Abstract
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.
Funder
National Institutes of Health
National Cancer Institute
Wellcome Trust
Department of Defense
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
302 articles.
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