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Ref Type Journal Article
PMID (31551363)
Authors Liang J, Zhao H, Diplas BH, Liu S, Liu J, Wang D, Lu Y, Zhu Q, Wu J, Wang W, Yan H, Zeng YX, Wang X, Jiao Y
Title Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of ATRX-Mutant Cancers to WEE1 Inhibition.
Journal Cancer research
Vol 80
Issue 3
Date 2020 Feb 01
URL
Abstract Text The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX. SIGNIFICANCE: ATRX-mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in ATRX-deficient cancers.See related commentary by Cole, p. 375.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATRX del hepatocellular carcinoma sensitive Adavosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Adavosertib (MK-1775) treatment resulted in cell cycle arrest, DNA damage, and apoptosis in hepatocellular carcinoma cell lines with ATRX gene knocked out via CRISPR-Cas9 in culture, and inhibited tumor growth in cell line xenograft models (PMID: 31551363). 31551363
ATRX R781* malignant glioma sensitive Adavosertib Preclinical - Patient cell culture Actionable In a preclinical study, Adavosertib (MK-1775) inhibited growth of patient-derived glioma cells harboring ATRX R781* in culture (PMID: 31551363). 31551363
ATRX S458* malignant glioma sensitive Adavosertib Preclinical - Patient cell culture Actionable In a preclinical study, Adavosertib (MK-1775) inhibited growth of patient-derived glioma cells harboring ATRX S458* in culture (PMID: 31551363). 31551363