title: PIK3CA-mutated melanoma cells rely on cooperative signaling through mTORC1/2 for sustained proliferation.
abstract: Malignant conversion of BRAF- or NRAS-mutated melanocytes into melanoma cells can be promoted by PI3'-lipid signaling. However, the mechanism by which PI3'-lipid signaling cooperates with mutationally activated BRAF or NRAS has not been adequately explored. Using human NRAS- or BRAF-mutated melanoma cells that co-express mutationally activated PIK3CA, we explored the contribution of PI3'-lipid signaling to cell proliferation. Despite mutational activation of PIK3CA, melanoma cells were more sensitive to the biochemical and antiproliferative effects of broader spectrum PI3K inhibitors than to an α-selective PI3K inhibitor. Combined pharmacological inhibition of MEK1/2 and PI3K signaling elicited more potent antiproliferative effects and greater inhibition of the cell division cycle compared to single-agent inhibition of either pathway alone. Analysis of signaling downstream of MEK1/2 or PI3K revealed that these pathways cooperate to regulate cell proliferation through mTORC1-mediated effects on ribosomal protein S6 and 4E-BP1 phosphorylation in an AKT-dependent manner. Although PI3K inhibition resulted in cytostatic effects on xenografted NRASQ61H/PIK3CAH1047Rmelanoma, combined inhibition of MEK1/2 plus PI3K elicited significant melanoma regression. This study provides insights as to how mutationally activated PIK3CA acts in concert with MEK1/2 signaling to cooperatively regulate mTORC1/2 to sustain PIK3CA-mutated melanoma proliferation.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Silva
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Marian M
authors.initials: MM
authors.lastname: Deuker
authors.affiliation: Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Martin
authors.identifier: 0000-0003-2812-1042
authors.initials: M
authors.lastname: McMahon
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: BRAF; MEK1/2; PIK3CA; mTORC1/2; melanoma