RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-02

AUTHORS

Zhan Yao, Yijun Gao, Wenjing Su, Rona Yaeger, Jessica Tao, Na Na, Ying Zhang, Chao Zhang, Andrey Rymar, Anthony Tao, Neilawattie M. Timaul, Rory Mcgriskin, Nathaniel A. Outmezguine, HuiYong Zhao, Qing Chang, Besnik Qeriqi, Mariano Barbacid, Elisa de Stanchina, David M Hyman, Gideon Bollag, Neal Rosen

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. More... »

PAGES

284-291

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41591-018-0274-5

DOI

http://dx.doi.org/10.1038/s41591-018-0274-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1110453070

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30559419


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