Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06958-9
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP-130540, PJT-156233]
- Merck, Sharpe & Dohme Corp./McGill Faculty of Medicine Grant for Translational Research
- Canadian Cancer Research Institute Innovation grant [702961]
- USA Department of Defense Office of Congressionally Directed Medical Research Grant [W81XWH-15-1-0497]
- CIHR Foundation Grant [FDN-148390, FDN-148366, FDN-143322]
- Cancer Research Society
- Small Cell Ovarian Cancer Foundation
- Fondation Gustave Roussy
- CIHR
- Maysie MacSporran Graduate Studentship
- Cedars Cancer Institute Fellowship
- CRC Chair in Functional Genomics
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Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16(INK4a)-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.
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