title: Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma.
abstract: Metabolic heterogeneity is a key factor in cancer pathogenesis. We found that a subset of BRAF- and NRAS-mutant human melanomas resistant to the MEK inhibitor selumetinib displayed increased oxidative phosphorylation (OxPhos) mediated by the transcriptional coactivator PGC1α. Notably, all selumetinib-resistant cells with elevated OxPhos could be resensitized by cotreatment with the mTORC1/2 inhibitor AZD8055, whereas this combination was ineffective in resistant cell lines with low OxPhos. In both BRAF- and NRAS-mutant melanoma cells, MEK inhibition increased MITF expression, which in turn elevated levels of PGC1α. In contrast, mTORC1/2 inhibition triggered cytoplasmic localization of MITF, decreasing PGC1α expression and inhibiting OxPhos. Analysis of tumor biopsies from patients with BRAF-mutant melanoma progressing on BRAF inhibitor ± MEK inhibitor revealed that PGC1α levels were elevated in approximately half of the resistant tumors. Overall, our findings highlight the significance of OxPhos in melanoma and suggest that combined targeting of the MAPK and mTORC pathways may offer an effective therapeutic strategy to treat melanomas with this metabolic phenotype.
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. vynanda@mdanderson.org.
authors.forename: Y N Vashisht
authors.initials: YN
authors.lastname: Gopal
authors.affiliation: Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dennie T
authors.initials: DT
authors.lastname: Frederick
authors.affiliation: Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia.
authors.forename: Gulietta
authors.initials: G
authors.lastname: Pupo
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinatti, Ohio.
authors.forename: Kakajan
authors.initials: K
authors.lastname: Komurov
authors.affiliation: Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Vasudha
authors.initials: V
authors.lastname: Sehgal
authors.affiliation: Department of Bioinformatics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Lalit
authors.initials: L
authors.lastname: Patel
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Cristiano G
authors.initials: CG
authors.lastname: Pereira
authors.affiliation: Department of Bioinformatics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Broom
authors.affiliation: Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Prahlad
authors.initials: P
authors.lastname: Ram
authors.affiliation: Astra Zeneca, Macclesfield, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases