Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma

Y. N.Vashisht Gopal, Helen Rizos, Guo Chen, Wanleng Deng, Dennie T. Frederick, Zachary A. Cooper, Richard A. Scolyer, Gulietta Pupo, Kakajan Komurov, Vasudha Sehgal, Jiexin Zhang, Lalit Patel, Cristiano G. Pereira, Bradley M. Broom, Gordon B. Mills, Prahlad Ram, Paul D. Smith, Jennifer A. Wargo, Georgina V. Long, Michael A. Davies

    Research output: Contribution to journalArticle

    78 Scopus citations

    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 combinationwas ineffective in resistant cell lines with lowOxPhos. 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.

    Original languageEnglish (US)
    Pages (from-to)7037-7047
    Number of pages11
    JournalCancer Research
    Volume74
    Issue number23
    DOIs
    StatePublished - Dec 1 2014

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Gopal, Y. N. V., Rizos, H., Chen, G., Deng, W., Frederick, D. T., Cooper, Z. A., Scolyer, R. A., Pupo, G., Komurov, K., Sehgal, V., Zhang, J., Patel, L., Pereira, C. G., Broom, B. M., Mills, G. B., Ram, P., Smith, P. D., Wargo, J. A., Long, G. V., & Davies, M. A. (2014). Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Research, 74(23), 7037-7047. https://doi.org/10.1158/0008-5472.CAN-14-1392