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.
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We thank T. Tieu for vector cloning; the MD Anderson core facilities, including the Sequencing and Microarray Facility (SMF), the Non-coding RNA and Sequencing Facility, the Genetically Engineered Mouse Facility (GEMF), S. Jiang and K. Zhao for assistance in maintenance of mouse colonies; T. Gutschner for discussion; and D. Spring for editing. This study was supported by the Cancer Prevention Research Institute (R120501 to P.A.F.) and the Welch Foundation’s Robert A. Welch Distinguished University Chair Award (G-0040 to P.A.F.). F.M. is supported by ACS grant RSG1514501CDD and CPRIT grant RP140612. This work was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program, the UT Lung SPORE 5 P50 CA07090, and the MD Anderson Cancer Center Support Grant P30CA01667. V.P is supported by R01CA155196-01A1 from the National Cancer Institute. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.
The authors declare no competing interests.
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Lissanu Deribe, Y., Sun, Y., Terranova, C. et al. Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer. Nat Med 24, 1047–1057 (2018). https://doi.org/10.1038/s41591-018-0019-5
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