title: Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma.
abstract: The MEK inhibitor MEK162 is the first targeted therapy agent with clinical activity in patients whose melanomas harbor NRAS mutations; however, median PFS is 3.7 months, suggesting the rapid onset of resistance in the majority of patients. Here, we show that treatment of NRAS-mutant melanoma cell lines with the MEK inhibitors AZD6244 or trametinib resulted in a rebound activation of phospho-ERK (pERK). Functionally, the recovery of signaling was associated with the maintenance of cyclin-D1 expression and therapeutic escape. The combination of a MEK inhibitor with an ERK inhibitor suppressed the recovery of cyclin-D1 expression and was associated with a significant enhancement of apoptosis and the abrogation of clonal outgrowth. The MEK/ERK combination strategy induced greater levels of apoptosis compared with dual MEK/CDK4 or MEK/PI3K inhibition across a panel of cell lines. These data provide the rationale for further investigation of vertically co-targeting the MAPK pathway as a potential treatment option for NRAS-mutant melanoma patients.
authors.affiliation: The Department of Molecular Oncology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Vito W
authors.initials: VW
authors.lastname: Rebecca
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Alicea
authors.forename: Kim H T
authors.initials: KH
authors.lastname: Paraiso
authors.forename: Harshani
authors.initials: H
authors.lastname: Lawrence
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: AZD6244; ERK; NRAS; melanoma; trametinib