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

Autor: Lissanu Deribe, Yonathan, Sun, Yuting, Terranova, Christopher, Khan, Fatima, Martinez-Ledesma, Juan, Gay, Jason, Gao, Guang, Mullinax, Robert, Khor, Tin, Feng, Ningping, Lin, Yu-Hsi, Wu, Chia-Chin, Reyes, Claudia, Peng, Qian, Robinson, Frederick, Inoue, Akira, Kochat, Veena, Liu, Chang-Gong, Asara, John, Moran, Cesar, Muller, Florian, Wang, Jing, Fang, Bingliang, Papadimitrakopoulou, Vali, Wistuba, Ignacio, Rai, Kunal, Marszalek, Joseph, Futreal, P.
Zdroj: Nature Medicine; July 2018, Vol. 24 Issue: 7 p1047-1057, 11p
Abstrakt: 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 SMARCA4and 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 Smarca4in the lung epithelium. We demonstrate that Smarca4acts as a bona fide tumor suppressor and cooperates with p53loss and Krasactivation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4mutant tumors. We further show that SMARCA4mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4mutant 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. SMARCA4 loss in non-small-cell lung cancer creates a metabolic dependency on oxidative phosphorylation that can be targeted using a new small-molecule inhibitor.
Databáze: Supplemental Index
Externí odkaz: