title: Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma.
abstract: The development of targeted inhibitors, vemurafenib and dabrafenib, has led to improved clinical outcome for melanoma patients with BRAFV600Emutations. 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 BRAFV600Emelanoma 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.
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Kircher
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|ARUP Laboratories, Salt Lake City, UT, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Grossmann
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: VanBrocklin
authors.affiliation: Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT, USA.|Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Holmen
authors.affiliation: Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Robinson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human