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

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, Hui Yong Zhao, Qing Chang, Besnik Qeriqi, Mariano Barbacid, Elisa de Stanchina, David M. Hyman, Gideon BollagNeal Rosen

Research output: Contribution to journalLetter

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 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 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.

Original languageEnglish (US)
Pages (from-to)284-291
Number of pages8
JournalNature medicine
Volume25
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

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Dimers
Monomers
Drug Resistance
Neoplasms
Protein Isoforms
Phosphotransferases
Fusion reactions
Alleles
Amino Acids
Tumors
Pharmaceutical Preparations
PLX8394

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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, Hui Yong; Chang, Qing; Qeriqi, Besnik; Barbacid, Mariano; de Stanchina, Elisa; Hyman, David M.; Bollag, Gideon; Rosen, Neal.

In: Nature medicine, Vol. 25, No. 2, 01.02.2019, p. 284-291.

Research output: Contribution to journalLetter

Yao, Z, Gao, Y, Su, W, Yaeger, R, Tao, J, Na, N, Zhang, Y, Zhang, C, Rymar, A, Tao, A, Timaul, NM, Mcgriskin, R, Outmezguine, NA, Zhao, HY, Chang, Q, Qeriqi, B, Barbacid, M, de Stanchina, E, Hyman, DM, Bollag, G & Rosen, N 2019, 'RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling', Nature medicine, vol. 25, no. 2, pp. 284-291. https://doi.org/10.1038/s41591-018-0274-5
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, Hui Yong ; 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. In: Nature medicine. 2019 ; Vol. 25, No. 2. pp. 284-291.
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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 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 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.",
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AU - Yaeger, Rona

AU - Tao, Jessica

AU - Na, Na

AU - Zhang, Ying

AU - Zhang, Chao

AU - Rymar, Andrey

AU - Tao, Anthony

AU - Timaul, Neilawattie M.

AU - Mcgriskin, Rory

AU - Outmezguine, Nathaniel A.

AU - Zhao, Hui Yong

AU - Chang, Qing

AU - Qeriqi, Besnik

AU - Barbacid, Mariano

AU - de Stanchina, Elisa

AU - Hyman, David M.

AU - Bollag, Gideon

AU - Rosen, Neal

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N2 - 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 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.

AB - 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 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.

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