Abstract:
:Ataxia telangiectasia mutated and RAD3 related (ATR) protein kinase plays critical roles in ensuring DNA replication, DNA repair, and cell cycle control in response to replication stress, making ATR inhibition a promising therapeutic strategy for cancer treatment. To identify genes whose loss makes tumor cells hypersensitive to ATR inhibition, we performed CRISPR/Cas9-based whole-genome screens in 3 independent cell lines treated with a highly selective ATR inhibitor, AZD6738. These screens uncovered a comprehensive genome-wide profile of ATR inhibitor sensitivity. From the candidate genes, we demonstrated that RNASEH2 deficiency is synthetic lethal with ATR inhibition both in vitro and in vivo. RNASEH2-deficient cells exhibited elevated levels of DNA damage and, when treated with AZD6738, underwent apoptosis (short-time treated) or senescence (long-time treated). Notably, RNASEH2 deficiency is frequently found in prostate adenocarcinoma; we found decreased RNASEH2B protein levels in prostate adenocarcinoma patient-derived xenograft (PDX) samples. Our findings suggest that ATR inhibition may be beneficial for cancer patients with reduced levels of RNASEH2 and that RNASEH2 merits further exploration as a potential biomarker for ATR inhibitor-based therapy.
journal_name
Oncogenejournal_title
Oncogeneauthors
Wang C,Wang G,Feng X,Shepherd P,Zhang J,Tang M,Chen Z,Srivastava M,McLaughlin ME,Navone NM,Hart GT,Chen Jdoi
10.1038/s41388-018-0606-4subject
Has Abstractpub_date
2019-04-01 00:00:00pages
2451-2463issue
14eissn
0950-9232issn
1476-5594pii
10.1038/s41388-018-0606-4journal_volume
38pub_type
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