Your browser doesn't support javascript.
loading
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer.
Lissanu Deribe, Yonathan; Sun, Yuting; Terranova, Christopher; Khan, Fatima; Martinez-Ledesma, Juan; Gay, Jason; Gao, Guang; Mullinax, Robert A; 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 M; Moran, Cesar; Muller, Florian; Wang, Jing; Fang, Bingliang; Papadimitrakopoulou, Vali; Wistuba, Ignacio I; Rai, Kunal; Marszalek, Joseph; Futreal, P Andrew.
Afiliação
  • Lissanu Deribe Y; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ylissanu@mdanderson.org.
  • Sun Y; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Terranova C; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Khan F; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Martinez-Ledesma J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Gay J; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Gao G; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mullinax RA; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Khor T; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Feng N; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lin YH; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wu CC; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Reyes C; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Peng Q; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Robinson F; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Inoue A; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Kochat V; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Liu CG; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Asara JM; Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • Moran C; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Muller F; Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wang J; Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Fang B; Department of Thoracic, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Papadimitrakopoulou V; Department of Thoracic, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wistuba II; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Rai K; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Marszalek J; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Futreal PA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Afutreal@mdanderson.org.
Nat Med ; 24(7): 1047-1057, 2018 07.
Article em En | MEDLINE | ID: mdl-29892061
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilação Oxidativa / Fatores de Transcrição / Proteínas Nucleares / DNA Helicases / Neoplasias Pulmonares / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilação Oxidativa / Fatores de Transcrição / Proteínas Nucleares / DNA Helicases / Neoplasias Pulmonares / Mutação Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article