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

• Verfasst von: Xue, Yibo [VerfasserIn]
• Verfasst von: Herpel, Esther [VerfasserIn]
• Titel: SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer
• Verf.angabe: 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 & Sidong Huang
• E-Jahr: 2019
• Jahr: 04 February 2019
• Umfang: 13 S.
• Fussnoten: Gesehen am 13.09.2019
• Titel Quelle: Enthalten in: Nature Communications
• Ort Quelle: [London] : Nature Publishing Group UK, 2010
• Jahr Quelle: 2019
• Band/Heft Quelle: 10(2019) Artikel-Nummer 557, 13 Seiten
• ISSN Quelle: 2041-1723
• DOI: doi:10.1038/s41467-019-08380-1
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1676928561

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.