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.

Keywords

PI3K/AKT/mTOR pathwayKinaseMelanomaCancer researchMEK inhibitorMAPK/ERK pathwayBiologyChemistrySignal transductionCell biology

MeSH Terms

Cell LineTumorDrug ResistanceNeoplasmHumansMAP Kinase Signaling SystemMelanomaMitogen-Activated Protein Kinase KinasesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsPhosphorylationProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-aktReceptorIGF Type 1raf Kinases

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Publication Info

Year: 2010
Type: article
Volume: 18
Issue: 6
Pages: 683-695
Citations: 1218
Access: Closed

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APA Style

                            
                                
                                    Jessie Villanueva, 
                                
                                    Adina Vultur, 
                                
                                    John Tayu Lee
                                
                                et al.
                            
                            (2010). 
                            Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K. 
                            Cancer Cell
                            , 18
                            (6)
                            , 683-695.
                            https://doi.org/10.1016/j.ccr.2010.11.023
                        

Identifiers

DOI: 10.1016/j.ccr.2010.11.023
PMID: 21156289
PMCID: PMC3026446

Data Quality

Data completeness: 90%