publication . Other literature type . Article . 2018

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

Jessica J. Tao; Ying Zhang; David M. Hyman; David M. Hyman; Nathaniel A. Outmezguine; Na Na; Gideon Bollag; Huiyong Zhao; Rory Mcgriskin; Chao Zhang; ...
Open Access
  • Published: 17 Dec 2018
  • Publisher: Springer Science and Business Media LLC
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-C...
Subjects
Medical Subject Headings: neoplasmsdigestive system diseasesendocrine system diseasesskin and connective tissue diseasesenzymes and coenzymes (carbohydrates)
free text keywords: Article, General Biochemistry, Genetics and Molecular Biology, General Medicine, Cell biology, Signal transduction, Gene isoform, Chemistry, Cell culture, Cooperative binding, Protein kinase domain, Mutant, Dimer, chemistry.chemical_compound, splice
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NIH| MOUSE GENETICS
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P30CA008748-43
  • Funding stream: NATIONAL CANCER INSTITUTE
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NIH| Studies on oncoprotein-induced feedback: Basic and therapeutic implications
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R35CA210085-02
  • Funding stream: NATIONAL CANCER INSTITUTE
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NIH| Mechanisms and Modulators of Sensitivity and Resistance to EGFR Inhibitors in Lu
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 5P01CA129243-07
  • Funding stream: NATIONAL CANCER INSTITUTE
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NIH| Cancer Chemotherapy Training Program
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 5T32CA009207-29
  • Funding stream: NATIONAL CANCER INSTITUTE
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