Combination of RAF and MEK inhibition for the treatment of BRAF-mutated melanoma: feedback is not encouraged

Paul B Chapman; David B Solit; Neal Rosen

doi:10.1016/j.ccell.2014.10.017

Combination of RAF and MEK inhibition for the treatment of BRAF-mutated melanoma: feedback is not encouraged

Cancer Cell. 2014 Nov 10;26(5):603-4. doi: 10.1016/j.ccell.2014.10.017. Epub 2014 Nov 10.

Authors

Paul B Chapman¹, David B Solit², Neal Rosen³

Affiliations

¹ Melanoma and Immunotherapeutics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: chapmanp@mskcc.org.
² Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.
³ Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA.

PMID: 25517746
DOI: 10.1016/j.ccell.2014.10.017

Abstract

In BRAF V600E melanoma patients, RAF inhibitor treatment causes a MEK-inhibitor-sensitive, RAF-inhibitor-resistant adaptive reactivation of ERK signaling. In clinical trials combining MEK and RAF inhibitors, therapeutic efficacy was modestly enhanced, suggesting the utility of inhibiting feedback-reactivated pathways. Strategies for optimally inhibiting ERK signaling should be explored.

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Feedback, Physiological
Humans
MAP Kinase Kinase Kinases / antagonists & inhibitors*
Melanoma / drug therapy*
Melanoma / genetics
Melanoma / mortality
Molecular Targeted Therapy
Mutation, Missense
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / genetics*
Randomized Controlled Trials as Topic
Signal Transduction

Substances

BRAF protein, human
Proto-Oncogene Proteins B-raf
MAP Kinase Kinase Kinases