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

Journal article


Publication Details

Author(s): 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
Journal: Nature Communications
Publication year: 2019
Volume: 10
ISSN: 2041-1723


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.


FAU Authors / FAU Editors

Rieker, Ralf Prof. Dr.
Pathologisches Institut


External institutions with authors

British Columbia Cancer Agency
Children's Hospital of Philadelphia
McGill University
Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
University of Michigan
University of Southern California (USC)


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).

BibTeX: 

Last updated on 2019-25-03 at 11:23