title: The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma.
abstract: Stimulation of the c-Kit receptor tyrosine kinase has a critical role in the development and migration of melanocytes, and oncogenic c-Kit mutants contribute to the progression of some melanomas. c-Kit signalling activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and their relative contribution to the activities of oncogenic and ligand-dependent c-Kit remains uncertain. We show that PI3K is a major regulator of MAPK activation in response to c-Kit activity and the dominant effector of c-Kit-driven melanocyte proliferation and melanoma survival. Nevertheless, inhibition of the PI3K pathway in c-Kit mutant melanoma cells did not replicate the apoptotic efficacy of the c-Kit inhibitor, imatinib mesylate. Instead, the simultaneous suppression of the PI3K and MAPK pathways promoted a strong synergistic apoptotic effect. These data indicate that MAPK functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Thus, the concurrent inhibition of PI3K and MAPK signalling is required to suppress oncogenic c-Kit activity and may provide an effective therapeutic strategy in c-Kit mutant melanomas.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: J R
authors.initials: JR
authors.lastname: Todd
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: L L
authors.initials: LL
authors.lastname: Scurr
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: T M
authors.initials: TM
authors.lastname: Becker
authors.affiliation: 1] Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia [2] Melanoma Institute Australia, Sydney, New South Wales, Australia.
authors.forename: R F
authors.initials: RF
authors.lastname: Kefford
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Rizos
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D001562:Benzimidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit; C517975:AZD 6244