期刊
CANCER CELL
卷 33, 期 6, 页码 1078-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.05.008
关键词
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资金
- Dutch Cancer Society [KWF 2011-5220, 2014-6532]
- Netherlands Organisation for Scientific Research [VICI 91814643]
- Netherlands Genomics Initiative [93512009]
- Cancer Research UK [C480/A1141, C5759/A17098]
- Danish Cancer Society
- Swedish Research Council
- Cancerfonden
- Danish National Research Foundation
- Swiss National Science Foundation [310030_156869]
- Swiss Cancer League [KLS-4282-08-2017]
- European Research Council [CoG-617485, CoG-681572, SyG-319661]
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.
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