Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer

被引：194

作者：

Deribe, Yonathan Lissanu ^{[1
]}

Sun, Yuting ^{[2
]}

Terranova, Christopher ^{[1
]}

Khan, Fatima ^{[1
]}

Martinez-Ledesma, Juan ^{[1
]}

Gay, Jason ^{[2
]}

Gao, Guang ^{[2
]}

Mullinax, Robert A. ^{[2
]}

Khor, Tin ^{[2
]}

Feng, Ningping ^{[2
]}

Lin, Yu-Hsi ^{[3
]}

Wu, Chia-Chin ^{[1
]}

Reyes, Claudia ^{[1
]}

Peng, Qian ^{[1
]}

Robinson, Frederick ^{[2
]}

Inoue, Akira ^{[1
]}

Kochat, Veena ^{[4
]}

Liu, Chang-Gong ^{[5
]}

Asara, John M. ^{[6
,7
]}

Moran, Cesar ^{[8
]}

Muller, Florian ^{[3
]}

Wang, Jing ^{[9
]}

Fang, Bingliang ^{[10
]}

Papadimitrakopoulou, Vali ^{[10
]}

Wistuba, Ignacio I. ^{[11
]}

Rai, Kunal ^{[1
]}

Marszalek, Joseph ^{[2
]}

Futreal, P. Andrew ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Canc Syst Imaging, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[6] Beth Israel Deaconess Med Ctr, Dept Med, Div Signal Transduct, Boston, MA USA

[7] Harvard Med Sch, Boston, MA USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 07期

关键词：

CHROMATIN-REMODELING FACTOR; TUMOR-SUPPRESSOR; METABOLISM; CELLS; BRG1; MYC; POLYCOMB; IMPAIRS; GENES;

D O I：

10.1038/s41591-018-0019-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.

引用

页码：1047 / +

页数：14