title: Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.
abstract: BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAF(V)⁶⁰⁰(E) melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Villanueva
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: John T
authors.initials: JT
authors.lastname: Lee
authors.forename: Rajasekharan
authors.initials: R
authors.lastname: Somasundaram
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.forename: Angela K
authors.initials: AK
authors.lastname: Cipolla
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Damien
authors.initials: D
authors.lastname: Kee
authors.forename: Ademi E
authors.initials: AE
authors.lastname: Santiago-Walker
authors.forename: Richard
authors.initials: R
authors.lastname: Letrero
authors.forename: Kurt
authors.initials: K
authors.lastname: D'Andrea
authors.forename: Anitha
authors.initials: A
authors.lastname: Pushparajan
authors.forename: James E
authors.initials: JE
authors.lastname: Hayden
authors.forename: Kimberly Dahlman
authors.initials: KD
authors.lastname: Brown
authors.forename: Sylvie
authors.initials: S
authors.lastname: Laquerre
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048490:raf Kinases / Q000502:physiology*
chemical_list: D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D048490:raf Kinases