BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition.
ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Zhan
Z
Yao
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Neilawattie M
NM
Torres
College of Arts and Sciences, New York University, New York, NY 10003, USA.
Anthony
A
Tao
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Yijun
Y
Gao
BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhong-Guan-Cun Life Science Park, Changping District, Beijing 102206, China.
Lusong
L
Luo
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Qi
Q
Li
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Elisa
E
de Stanchina
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Omar
O
Abdel-Wahab
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
David B
DB
Solit
Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Poulikos I
PI
Poulikakos
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Mechanism Based Therapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rosenn@mskcc.org.
Neal
N
Rosen
D045744:Cell Line, Tumor; D019281:Dimerization; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins