Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.
复制标题
DOI：
10.1038/s41591-018-0019-5
复制
发表时间：
2018-07
期刊：
影响因子：
82.9
通讯作者：
Futreal PA
中科院分区：
文献类型：
--
作者：
Lissanu Deribe Y;Sun Y;Terranova C;Khan F;Martinez-Ledesma J;Gay J;Gao G;Mullinax RA;Khor T;Feng N;Lin YH;Wu CC;Reyes C;Peng Q;Robinson F;Inoue A;Kochat V;Liu CG;Asara JM;Moran C;Muller F;Wang J;Fang B;Papadimitrakopoulou V;Wistuba II;Rai K;Marszalek J;Futreal PA
肺癌是一种毁灭性的疾病，仍然是癌症死亡的首要原因。尽管靶向治疗和免疫治疗有所改善，但大多数肺癌患者缺乏有效的治疗方法，这突显了需要更多的治疗方法。基因组研究发现，SWI/SNF染色质重塑复合体的成分经常发生变化，包括SMARCA4和ARID1A。为了了解这种复合体突变驱动的肿瘤发生机制，我们通过去除肺上皮中的SMARCA4建立了一种基因工程小鼠肺腺癌模型。我们证明SMARCA4是一种真正的肿瘤抑制因子，并与P53丢失和Kras激活协同作用。基因表达分析显示SMARCA4突变肿瘤具有增强氧化磷酸化(OXPHOS)的特征。我们进一步表明，SMARCA4突变细胞增加了氧气消耗和呼吸能力。重要的是，SMARCA4突变的肺癌细胞系和异种移植瘤对正在临床开发中的一种新的小分子IacS-010759抑制氧磷脂具有显著的敏感性。从机制上讲，我们证明了SMARCA4缺陷细胞对能量压力的转录反应迟钝，创造了一种可用于治疗的合成致命相互作用。这些发现为进一步开发OXPHOS抑制剂作为治疗SWI/SNF突变肿瘤的药物提供了机制基础。
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 more therapeutics. 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 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.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
30.8
作者：
Mathur R;Alver BH;San Roman AK;Wilson BG;Wang X;Agoston AT;Park PJ;Shivdasani RA;Roberts CW
通讯作者：
Roberts CW
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
28.2
作者：
Kim ES;Herbst RS;Wistuba II;Lee JJ;Blumenschein GR Jr;Tsao A;Stewart DJ;Hicks ME;Erasmus J Jr;Gupta S;Alden CM;Liu S;Tang X;Khuri FR;Tran HT;Johnson BE;Heymach JV;Mao L;Fossella F;Kies MS;Papadimitrakopoulou V;Davis SE;Lippman SM;Hong WK
通讯作者：
Hong WK