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

Xue Y, Meehan B, Fu Z, Wang XQD, Fiset PO, Rieker R, Levins C, Kong T, Zhu X, Morin G, Skerritt L, Herpel E, Venneti S, Martinez D, Judkins AR, Jung S, Camilleri-Broet S, Gonzalez AV, Guiot MC, Lockwood WW, Spicer JD, Agaimy A, Pastor WA, Dostie J, Rak J, Foulkes WD, Huang S (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 10

Article Number: ARTN 557

DOI: 10.1038/s41467-019-08380-1

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.

Authors with CRIS profile

Ralf Rieker Institute of Pathology

Involved external institutions

McGill University CA Canada (CA) Children's Hospital of Philadelphia US United States (USA) (US) University of Southern California (USC) US United States (USA) (US) British Columbia Cancer Agency CA Canada (CA) University of Michigan US United States (USA) (US) Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg DE Germany (DE)

How to cite

APA:

Xue, Y., Meehan, B., Fu, Z., Wang, X.Q.D., Fiset, P.O., Rieker, R.,... Huang, S. (2019). SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nature Communications, 10. https://dx.doi.org/10.1038/s41467-019-08380-1

MLA:

Xue, Yibo, et al. "SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer." Nature Communications 10 (2019).

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