ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells
- Stephanie A. Yazinski1,
- Valentine Comaills1,6,
- Rémi Buisson1,6,
- Marie-Michelle Genois1,6,
- Hai Dang Nguyen1,
- Chu Kwen Ho1,
- Tanya Todorova Kwan1,2,
- Robert Morris1,
- Sam Lauffer1,3,
- André Nussenzweig4,
- Sridhar Ramaswamy1,
- Cyril H. Benes1,
- Daniel A. Haber1,2,
- Shyamala Maheswaran1,
- Michael J. Birrer1,3 and
- Lee Zou1,5
- 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
- 2Howard Hughes Medical Institute, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA;
- 3Massachusetts General Hospital Gillette Center, Massachusetts General Hospital, Boston, Massachusetts 02115, USA;
- 4Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
- 5Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
- Corresponding author: zou.lee{at}mgh.harvard.edu
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↵6 These authors contributed equally to this work.
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.290957.116.
- Received September 19, 2016.
- Accepted January 31, 2017.
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