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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: 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
Zeitschrift: Nature Communications
Jahr der Veröffentlichung: 2019
Band: 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-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Rieker, Ralf Prof. Dr.
Pathologisches Institut


Einrichtungen weiterer Autorinnen und Autoren

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)


Zitierweisen

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: 

Zuletzt aktualisiert 2019-25-03 um 11:23