Journal Article

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

Liu, Chang-Gong, Futreal, P. Andrew, Fang, Bingliang, Terranova, Christopher, Wu, Chia-Chin, Marszalek, Joseph, Sun, Yuting, Inoue, Akira, Asara, John M., Reyes, Claudia, Muller, Florian, Wistuba, Ignacio I., Gay, Jason, Mullinax, Robert A., Kochat, Veena, Robinson, Frederick, Khan, Fatima, Wang, Jing, Papadimitrakopoulou, Vali, Lissanu Deribe, Yonathan, Feng, Ningping, Peng, Qian, Rai, Kunal, Gao, Guang, Moran, Cesar, Khor, Tin, Martinez-Ledesma, Juan, Lin, Yu-Hsi

2018

Overview

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. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adenocarcinoma / Animals / Biomedical and Life Sciences / Biomedicine / Biosynthetic Pathways / Cancer / Cancer cells / Cancer patients / Cancer Research / Cancer treatment / Care and treatment / Cell Line, Tumor / Cell Respiration / Chromatin / Chromatin remodeling / Dependence / DNA Helicases - deficiency / DNA Helicases - genetics / Energy Metabolism / Epithelium / Female / Gene expression / Gene mutation / Genetic aspects / Genetic Engineering / Genetic research / Genetically modified organisms / Humans / Immunotherapy / Infectious Diseases / Lung cancer / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Metabolic Diseases / Mice, Nude / Mitochondria - metabolism / Molecular chains / Molecular Medicine / Mortality / Mutants / Mutation / Mutation - genetics / Neurosciences / Non-small cell lung cancer / Nuclear Proteins - deficiency / Nuclear Proteins - genetics / Oxidative Phosphorylation / Oxygen consumption / p53 Protein / Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism / Phosphorylation / RNA sequencing / Stress, Physiological - genetics / SWI/SNF complex / Transcription / Transcription Factors - deficiency / Transcription Factors - genetics / Tumor cell lines / Tumor proteins / Tumor suppressor genes / Tumorigenesis / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation