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

Yibo Xue, Brian Meehan, Zheng Fu, Xue Qing D. Wang, Pierre Olivier Fiset, Ralf Rieker, Cameron Levins, Tim Kong, Xianbing Zhu, Geneviève Morin, Lashanda Skerritt, Esther Herpel, Sriram Venneti, Daniel Martinez, Alexander R. Judkins, Sungmi Jung, Sophie Camilleri-Broet, Anne V. Gonzalez, Marie-Christine Guiot, William W. Lockwood, Jonathan D. Spicer, Abbas Agaimy, William A. Pastor, Josée Dostie, Janusz Rak, William D. Foulkes and Sidong Huang ()
Additional contact information
Yibo Xue: McGill University
Brian Meehan: Montreal Children’s Hospital
Zheng Fu: McGill University
Xue Qing D. Wang: McGill University
Pierre Olivier Fiset: McGill University Health Centre
Ralf Rieker: University Hospital
Cameron Levins: McGill University
Tim Kong: McGill University
Xianbing Zhu: McGill University
Geneviève Morin: McGill University
Lashanda Skerritt: McGill University
Esther Herpel: Heidelberg University Hospital
Sriram Venneti: University of Michigan Medical School
Daniel Martinez: Children’s Hospital of Philadelphia Research Institute
Alexander R. Judkins: Keck School of Medicine of University of Southern California
Sungmi Jung: McGill University Health Centre
Sophie Camilleri-Broet: McGill University Health Centre
Anne V. Gonzalez: McGill University Health Centre
Marie-Christine Guiot: McGill University Health Centre
William W. Lockwood: British Columbia Cancer Agency
Jonathan D. Spicer: McGill University Health Center
Abbas Agaimy: University Hospital
William A. Pastor: McGill University
Josée Dostie: McGill University
Janusz Rak: Montreal Children’s Hospital
William D. Foulkes: McGill University
Sidong Huang: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08380-1

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