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Nat Commun. 2019 Feb 4;10(1):558. doi: 10.1038/s41467-018-06958-9.

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.

Author information

1
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
2
The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
3
Department of Pediatrics, McGill University, Montreal, QC, H4A 3J1, Canada.
4
Research Institute of McGill University Health Centre Montreal Children's Hospital, Montreal, QC, H4A 3J1, Canada.
5
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1Y 4E9, Canada.
6
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
7
Pathology and Neuropathology, University of Michigan Medical School, Ann Arbor, MI, 48109-0605, USA.
8
Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada.
9
Department of Medical Genetics, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
10
Lady Davis Institute, McGill University, Montreal, QC, H3T 1E2, Canada.
11
Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3JI, Canada.
12
Gynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, 10016, USA.
13
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
14
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sat University, 510275, Guangzhou, China.
15
Department of Cancer Medicine, Gustave Roussy, INSERM U981, 94800, Villejuif, France.
16
Genomics Core Facility, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
17
Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
18
Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON, M5G 2C4, Canada.
19
Department of Oncology, McGill University, Montreal, QC, H3T 1E2, Canada.
20
Department of Experimental Medicine, McGill University, Montreal, QC, H3T 1E2, Canada.
21
Lady Davis Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
22
Segal Cancer Centre, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
23
Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, QC, H3A 2B4, Canada.
24
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90027, USA.
25
Biochemistry and Tumor Biology Laboratory, Department of Gynecology and Obstetrics, Medical University Hannover, 30625, Hannover, Germany.
26
Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada. william.foulkes@mcgill.ca.
27
Department of Medical Genetics, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada. william.foulkes@mcgill.ca.
28
Lady Davis Institute, McGill University, Montreal, QC, H3T 1E2, Canada. william.foulkes@mcgill.ca.
29
Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3JI, Canada. william.foulkes@mcgill.ca.
30
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada. sidong.huang@mcgill.ca.
31
The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada. sidong.huang@mcgill.ca.

Abstract

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/p16INK4a-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.

PMID:
30718512
PMCID:
PMC6361890
DOI:
10.1038/s41467-018-06958-9
[Indexed for MEDLINE]
Free PMC Article

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