Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

H. Yang, D A Kircher, K. H. Kim, A H Grossmann, M W VanBrocklin, S L Holmen, J P Robinson

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Abstract

The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes causing complete tumor regression, the majority of melanomas eventually become resistant. Mitogen-activated protein kinase kinase (MEK) mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to targeted therapy; however, melanoma is a molecularly heterogeneous cancer, and which mutations are drivers and which are passengers remains to be determined. In this study, we demonstrate that in BRAFV600E melanoma cell lines, activating MEK mutations drive resistance and contribute to suboptimal growth of melanoma cells following the withdrawal of BRAF inhibition. In this manner, the cells are drug-addicted, suggesting that melanoma cells evolve a ‘just right’ level of mitogen-activated protein kinase signaling and the additive effects of MEK and BRAF mutations are counterproductive. We also used a novel mouse model of melanoma to demonstrate that several of these MEK mutants promote the development, growth and maintenance of melanoma in vivo in the context of Cdkn2a and Pten loss. By utilizing a genetic approach to control mutant MEK expression in vivo, we were able to induce tumor regression and significantly increase survival; however, after a long latency, all tumors subsequently became resistant. These data suggest that resistance to BRAF or MEK inhibitors is probably inevitable, and novel therapeutic approaches are needed to target dormant tumors.
Original languageEnglish (US)
Pages (from-to)3842-3851
Number of pages10
JournalOncogene
Volume36
Issue number27
DOIs
StatePublished - Jul 2017

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    Yang, H., Kircher, D. A., Kim, K. H., Grossmann, A. H., VanBrocklin, M. W., Holmen, S. L., & Robinson, J. P. (2017). Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma. Oncogene, 36(27), 3842-3851. https://doi.org/10.1038/onc.2016.526