151. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling
- Author
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Qing Chang, Chao Zhang, Nathaniel A. Outmezguine, Jessica J. Tao, Mariano Barbacid, Yijun Gao, Neal Rosen, Andrey Rymar, Neilawattie M. Timaul, Rory Mcgriskin, Besnik Qeriqi, Elisa de Stanchina, Anthony Tao, Rona Yaeger, David M. Hyman, Na Na, Gideon Bollag, Hui Yong Zhao, Ying Zhang, Zhan Yao, and Wenjing Su
- Subjects
0301 basic medicine ,Gene isoform ,Proto-Oncogene Proteins B-raf ,endocrine system diseases ,Mutant ,Heterocyclic Compounds, 2-Ring ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Humans ,Phosphorylation ,skin and connective tissue diseases ,Extracellular Signal-Regulated MAP Kinases ,neoplasms ,Cell Proliferation ,Sulfonamides ,Kinase ,Chemistry ,Cooperative binding ,General Medicine ,digestive system diseases ,Cell biology ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,Protein kinase domain ,Cell culture ,030220 oncology & carcinogenesis ,Mutation ,Signal transduction ,Protein Multimerization ,Function (biology) ,Signal Transduction - Abstract
Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers1. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer1–3. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize4–8. We show here that PLX8394, a new RAF inhibitor9, inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF–CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions. The new RAF inhibitor PLX8394 selectively blocks ERK signaling in tumors driven by class 1 and/or class 2 BRAF mutations and BRAF fusions while maintaining a broad therapeutic window.
- Published
- 2017