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Nat Commun. 2019 Feb 4;10(1):557. doi: 10.1038/s41467-019-08380-1.

SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer.

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, and Research Institute of McGill University Health Centre, Montreal Children's Hospital, Montreal, QC, H4A 3J1, Canada.
4
Department of Pathology, Glen Site, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
5
Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, 91054, Erlangen, Germany.
6
Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada.
7
Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, and Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
8
Pathology and Neuropathology, University of Michigan Medical School, Ann Arbor, MI, 48109-0605, USA.
9
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
10
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.
11
Division of Respiratory Medicine, Montreal Chest Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
12
Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
13
Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
14
Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada.
15
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
16
Department of Surgery, McGill University Health Center, Montreal, QC, H4A 3J1, Canada.
17
Department of Medical Genetics, and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
18
Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3J1, Canada.
19
Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada. sidong.huang@mcgill.ca.
20
The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada. sidong.huang@mcgill.ca.

Abstract

Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodeling gene, is frequently inactivated in cancers and is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA4/2 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-Jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

PMID:
30718506
PMCID:
PMC6362083
DOI:
10.1038/s41467-019-08380-1
[Indexed for MEDLINE]
Free PMC Article

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