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

被引：146

作者：

Xue, Yibo ^{[1
,2
]}

Meehan, Brian ^{[3
,4
]}

Fu, Zheng ^{[1
,2
]}

Wang, Xue Qing D. ^{[1
]}

Fiset, Pierre Olivier ^{[5
]}

Rieker, Ralf ^{[6
]}

Levins, Cameron ^{[7
]}

Kong, Tim ^{[1
,2
]}

Zhu, Xianbing ^{[1
,2
]}

Morin, Genevieve ^{[1
,2
]}

Skerritt, Lashanda ^{[1
,2
]}

Herpel, Esther ^{[8
,9
]}

Venneti, Sriram ^{[10
]}

Martinez, Daniel ^{[11
]}

Judkins, Alexander R. ^{[12
]}

Jung, Sungmi ^{[5
]}

Camilleri-Broet, Sophie ^{[5
]}

Gonzalez, Anne V. ^{[13
]}

Guiot, Marie-Christine ^{[14
]}

Lockwood, William W. ^{[15
,16
,17
]}

Spicer, Jonathan D. ^{[18
]}

Agaimy, Abbas ^{[5
]}

Pastor, William A. ^{[1
,2
,19
,20
,21
,22
]}

Dostie, Josee ^{[1
]}

Rak, Janusz ^{[3
]}

Foulkes, William D. ^{[6
]}

Huang, Sidong ^{[1
,2
]}

机构：

[1] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[2] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[3] McGill Univ, Dept Pediat, Montreal, PQ H4A 3J1, Canada

[4] McGill Univ, Hlth Ctr, Res Inst, Montreal Childrens Hosp, Montreal, PQ H4A 3J1, Canada

[5] McGill Univ, Hlth Ctr, Dept Pathol, Glen Site, Montreal, PQ H4A 3J1, Canada

[6] Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp, Inst Pathol, D-91054 Erlangen, Germany

[7] McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada

[8] Natl Ctr Tumor Dis NCT Heidelberg, Tissue Bank, D-69120 Heidelberg, Germany

[9] Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany

[10] Univ Michigan, Med Sch, Pathol & Neuropathol, Ann Arbor, MI 48109 USA

[11] Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USA

[12] Univ Southern Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90027 USA

[13] McGill Univ, Hlth Ctr, Montreal Chest Inst, Div Resp Med, Montreal, PQ H4A 3J1, Canada

[14] McGill Univ, Hlth Ctr, Montreal Neurol Hosp Inst, Dept Pathol, Montreal, PQ H4A 3J1, Canada

[15] British Columbia Canc Agcy, Dept Integrat Oncol, Vancouver, BC V5Z 1L3, Canada

[16] Univ British Columbia, Interdisciplinary Oncol Program, Vancouver, BC V6T 1Z2, Canada

[17] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada

[18] McGill Univ, Hlth Ctr, Dept Surg, Montreal, PQ H4A 3J1, Canada

[19] McGill Univ, Jewish Gen Hosp, Dept Med Genet, Montreal, PQ H3T 1E2, Canada

[20] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada

[21] McGill Univ, Hlth Ctr, Res Inst, Dept Med Genet, Montreal, PQ H4A 3J1, Canada

[22] McGill Univ, Hlth Ctr, Res Inst, Canc Res Program, Montreal, PQ H4A 3J1, Canada

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院;

关键词：

DEPENDENT KINASE INHIBITOR; CYCLIN D1 PROMOTER; REGULATORY ELEMENTS; HYPERCALCEMIC TYPE; OPEN CHROMATIN; BREAST-CANCER; CARCINOMA; MUTATIONS; OVARY; PALBOCICLIB;

D O I：

10.1038/s41467-019-08380-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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