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

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 monomers(1). Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimer...

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Autores principales: Yao, Zhan, Gao, Yijun, Su, Wenjing, Yaeger, Rona, Tao, Jessica, Na, Na, Zhang, Ying, Zhang, Chao, Rymar, Andrey, Tao, Anthony, Timaul, Neilawattie M., Mcgriskin, Rory, Outmezguine, Nathaniel A., Zhao, HuiYong, Chang, Qing, Qeriqi, Besnik, Barbacid, Mariano, de Stanchina, Elisa, Hyman, David M, Bollag, Gideon, Rosen, Neal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404779/
https://www.ncbi.nlm.nih.gov/pubmed/30559419
http://dx.doi.org/10.1038/s41591-018-0274-5
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author Yao, Zhan
Gao, Yijun
Su, Wenjing
Yaeger, Rona
Tao, Jessica
Na, Na
Zhang, Ying
Zhang, Chao
Rymar, Andrey
Tao, Anthony
Timaul, Neilawattie M.
Mcgriskin, Rory
Outmezguine, Nathaniel A.
Zhao, HuiYong
Chang, Qing
Qeriqi, Besnik
Barbacid, Mariano
de Stanchina, Elisa
Hyman, David M
Bollag, Gideon
Rosen, Neal
author_facet Yao, Zhan
Gao, Yijun
Su, Wenjing
Yaeger, Rona
Tao, Jessica
Na, Na
Zhang, Ying
Zhang, Chao
Rymar, Andrey
Tao, Anthony
Timaul, Neilawattie M.
Mcgriskin, Rory
Outmezguine, Nathaniel A.
Zhao, HuiYong
Chang, Qing
Qeriqi, Besnik
Barbacid, Mariano
de Stanchina, Elisa
Hyman, David M
Bollag, Gideon
Rosen, Neal
author_sort Yao, Zhan
collection PubMed
description 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 monomers(1). 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 dimer(1–3). Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize(4–8). We show here that PLX8394, a new RAF inhibitor(9), 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 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 and as well 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.
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spelling pubmed-64047792019-06-17 RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling Yao, Zhan Gao, Yijun Su, Wenjing Yaeger, Rona Tao, Jessica Na, Na Zhang, Ying Zhang, Chao Rymar, Andrey Tao, Anthony Timaul, Neilawattie M. Mcgriskin, Rory Outmezguine, Nathaniel A. Zhao, HuiYong Chang, Qing Qeriqi, Besnik Barbacid, Mariano de Stanchina, Elisa Hyman, David M Bollag, Gideon Rosen, Neal Nat Med Article 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 monomers(1). 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 dimer(1–3). Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize(4–8). We show here that PLX8394, a new RAF inhibitor(9), 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 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 and as well 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. 2018-12-17 2019-02 /pmc/articles/PMC6404779/ /pubmed/30559419 http://dx.doi.org/10.1038/s41591-018-0274-5 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Yao, Zhan
Gao, Yijun
Su, Wenjing
Yaeger, Rona
Tao, Jessica
Na, Na
Zhang, Ying
Zhang, Chao
Rymar, Andrey
Tao, Anthony
Timaul, Neilawattie M.
Mcgriskin, Rory
Outmezguine, Nathaniel A.
Zhao, HuiYong
Chang, Qing
Qeriqi, Besnik
Barbacid, Mariano
de Stanchina, Elisa
Hyman, David M
Bollag, Gideon
Rosen, Neal
RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title_full RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title_fullStr RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title_full_unstemmed RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title_short RAF inhibitor PLX8394 selectively disrupts BRAF-dimers and RAS-independent BRAF mutant-driven signaling
title_sort raf inhibitor plx8394 selectively disrupts braf-dimers and ras-independent braf mutant-driven signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404779/
https://www.ncbi.nlm.nih.gov/pubmed/30559419
http://dx.doi.org/10.1038/s41591-018-0274-5
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