PMID- 25297634 OWN - NLM STAT- MEDLINE DCOM- 20150304 LR - 20211203 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 74 IP - 23 DP - 2014 Dec 1 TI - Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. PG - 7037-47 LID - 10.1158/0008-5472.CAN-14-1392 [doi] AB - 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 PGC1alpha. 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 PGC1alpha. In contrast, mTORC1/2 inhibition triggered cytoplasmic localization of MITF, decreasing PGC1alpha expression and inhibiting OxPhos. Analysis of tumor biopsies from patients with BRAF-mutant melanoma progressing on BRAF inhibitor +/- MEK inhibitor revealed that PGC1alpha 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. CI - (c)2014 American Association for Cancer Research. FAU - Gopal, Y N Vashisht AU - Gopal YN AD - Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. vynanda@mdanderson.org. FAU - Rizos, Helen AU - Rizos H AD - Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia. FAU - Chen, Guo AU - Chen G AD - Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Deng, Wanleng AU - Deng W AD - Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Frederick, Dennie T AU - Frederick DT AD - Massachusetts General Hospital, Boston, Massachusetts. FAU - Cooper, Zachary A AU - Cooper ZA AD - Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Scolyer, Richard A AU - Scolyer RA AD - Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia. FAU - Pupo, Gulietta AU - Pupo G AD - Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia. FAU - Komurov, Kakajan AU - Komurov K AD - Department of Pediatrics, University of Cincinnati, Cincinatti, Ohio. FAU - Sehgal, Vasudha AU - Sehgal V AD - Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Zhang, Jiexin AU - Zhang J AD - Department of Bioinformatics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Patel, Lalit AU - Patel L AD - Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Pereira, Cristiano G AU - Pereira CG AD - Departments of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Broom, Bradley M AU - Broom BM AD - Department of Bioinformatics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Mills, Gordon B AU - Mills GB AD - Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Ram, Prahlad AU - Ram P AD - Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Smith, Paul D AU - Smith PD AD - Astra Zeneca, Macclesfield, United Kingdom. FAU - Wargo, Jennifer A AU - Wargo JA AD - Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Long, Georgina V AU - Long GV AD - Melanoma Institute of Australia and Westmead Hospital, Sydney, Australia. FAU - Davies, Michael A AU - Davies MA AD - 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. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P50 CA093459/CA/NCI NIH HHS/United States GR - CA16672/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20141008 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (MITF protein, human) RN - 0 (Microphthalmia-Associated Transcription Factor) RN - 0 (Multiprotein Complexes) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Transcription Factors) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) SB - IM MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - MAP Kinase Signaling System/*drug effects MH - Mechanistic Target of Rapamycin Complex 1 MH - Mechanistic Target of Rapamycin Complex 2 MH - Melanoma/*drug therapy/genetics/metabolism MH - Microphthalmia-Associated Transcription Factor/genetics/metabolism MH - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/genetics/metabolism MH - Multiprotein Complexes/*antagonists & inhibitors/genetics/metabolism MH - Oxidative Phosphorylation/*drug effects MH - Protein Kinase Inhibitors/*pharmacology MH - Proto-Oncogene Proteins B-raf/genetics/metabolism MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/genetics/metabolism MH - Transcription Factors/genetics/metabolism PMC - PMC4347853 MID - NIHMS633085 EDAT- 2014/10/10 06:00 MHDA- 2015/03/05 06:00 PMCR- 2015/12/01 CRDT- 2014/10/10 06:00 PHST- 2014/10/10 06:00 [entrez] PHST- 2014/10/10 06:00 [pubmed] PHST- 2015/03/05 06:00 [medline] PHST- 2015/12/01 00:00 [pmc-release] AID - 0008-5472.CAN-14-1392 [pii] AID - 10.1158/0008-5472.CAN-14-1392 [doi] PST - ppublish SO - Cancer Res. 2014 Dec 1;74(23):7037-47. doi: 10.1158/0008-5472.CAN-14-1392. Epub 2014 Oct 8.