The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Inhibition of mTORC1/2 Overcomes Resistance to MAPK Pathway Inhibitors Mediated by PGC1α and Oxidative Phosphorylation in Melanoma
Open accessAbstract
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. Cancer Res; 74(23); 7037–47. ©2014 AACR.
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Cites
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
Drug combination studies and their synergy quantification using the Chou-Talalay method
Chou, T.-C. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1947 · Cited by 5,739
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib
Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112302 · Cited by 2,156
Metabolic control through the PGC-1 family of transcription coactivators
Lin, J., Handschin, C., & Spiegelman, B. M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.004 · Cited by 2,130 · cited 1×
“PGC1a is a transcriptional coactivator that induces multiple genes involved in mitochondrial OxPhos and increases mitochondrial biogenesis (18).”
BackgroundmTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex
Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., & Puigserver, P. (2007) · Nature · doi:10.1038/nature06322 · Cited by 1,488
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818
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Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Targeted agents and immunotherapies: optimizing outcomes in melanoma
Luke, J. J., Flaherty, K. T., Ribas, A., & Long, G. V. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.43 · Cited by 1,254
Self-citationToward Minimal Residual Disease-Directed Therapy in Melanoma
Rambow, F., Rogiers, A., Marin-Bejar, O., Aibar, S., Femel, J., Dewaele, M., Karras, P., Brown, D., Chang, Y. H., Debiec-Rychter, M., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.025 · Cited by 771
Self-citationMcQuade, J. L., Daniel, C. R., Hess, K. R., Mak, C., Wang, D. Y., Rai, R. R., Park, J. J., Haydu, L. E., Spencer, C., Wongchenko, M., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30078-0 · Cited by 664
Self-citationBasit, F., van Oppen, L. M., Schöckel, L., Bossenbroek, H. M., van Emst-de Vries, S. E., Hermeling, J. C., Grefte, S., Kopitz, C., Heroult, M., HGM Willems, P., et al. (2017) · Cell Death & Disease · doi:10.1038/cddis.2017.133 · Cited by 565
Metadata
- Authors
- 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.
- Venue
- Cancer Research
- Published
- 2014-11-30
- Volume
- 74
- Issue
- 23
- Pages
- 7037-7047
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2104697581
- Cited by
- 201
- References
- 6
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- 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. https://doi.org/10.1158/0008-5472.can-14-1392
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