Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors

Jaehyuk Choi*, Sean F. Landrette, Tiffany Wang, Perry Evans, Antonella Bacchiocchi, Robert Bjornson, Elaine Cheng, Amy L. Stiegler, Symon Gathiaka, Orlando Acevedo, Titus J. Boggon, Michael Krauthammer, Ruth Halaban, Tian Xu

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF V600K melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF L505H ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF L505H , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalPigment Cell and Melanoma Research
Volume27
Issue number2
DOIs
StatePublished - Mar 1 2014

Fingerprint

Mutation
Melanoma
Mutagenesis
Aberrations
Exome
Screening
Substitution reactions
Genes
Amino Acids
PLX4032
Prostatic Neoplasms
Clinical Trials
Pharmaceutical Preparations
Genome
Survival
Therapeutics
PLX8394

Keywords

  • BRAF
  • Drug resistance
  • Melanoma
  • PLX4032
  • Paradox blockers

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

Cite this

Choi, J., Landrette, S. F., Wang, T., Evans, P., Bacchiocchi, A., Bjornson, R., ... Xu, T. (2014). Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. Pigment Cell and Melanoma Research, 27(2), 253-262. https://doi.org/10.1111/pcmr.12197
Choi, Jaehyuk ; Landrette, Sean F. ; Wang, Tiffany ; Evans, Perry ; Bacchiocchi, Antonella ; Bjornson, Robert ; Cheng, Elaine ; Stiegler, Amy L. ; Gathiaka, Symon ; Acevedo, Orlando ; Boggon, Titus J. ; Krauthammer, Michael ; Halaban, Ruth ; Xu, Tian. / Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. In: Pigment Cell and Melanoma Research. 2014 ; Vol. 27, No. 2. pp. 253-262.
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Choi, J, Landrette, SF, Wang, T, Evans, P, Bacchiocchi, A, Bjornson, R, Cheng, E, Stiegler, AL, Gathiaka, S, Acevedo, O, Boggon, TJ, Krauthammer, M, Halaban, R & Xu, T 2014, 'Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors', Pigment Cell and Melanoma Research, vol. 27, no. 2, pp. 253-262. https://doi.org/10.1111/pcmr.12197

Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. / Choi, Jaehyuk; Landrette, Sean F.; Wang, Tiffany; Evans, Perry; Bacchiocchi, Antonella; Bjornson, Robert; Cheng, Elaine; Stiegler, Amy L.; Gathiaka, Symon; Acevedo, Orlando; Boggon, Titus J.; Krauthammer, Michael; Halaban, Ruth; Xu, Tian.

In: Pigment Cell and Melanoma Research, Vol. 27, No. 2, 01.03.2014, p. 253-262.

Research output: Contribution to journalArticle

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T1 - Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors

AU - Choi, Jaehyuk

AU - Landrette, Sean F.

AU - Wang, Tiffany

AU - Evans, Perry

AU - Bacchiocchi, Antonella

AU - Bjornson, Robert

AU - Cheng, Elaine

AU - Stiegler, Amy L.

AU - Gathiaka, Symon

AU - Acevedo, Orlando

AU - Boggon, Titus J.

AU - Krauthammer, Michael

AU - Halaban, Ruth

AU - Xu, Tian

PY - 2014/3/1

Y1 - 2014/3/1

N2 - BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF V600K melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF L505H ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF L505H , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.

AB - BRAF inhibitors improve melanoma patient survival, but resistance invariably develops. Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF V600K melanoma cells. We further describe a new screening approach, a genome-wide piggyBac mutagenesis screen that revealed clinically relevant aberrations (N-terminal BRAF truncations and CRAF overexpression). The novel BRAF mutation, a Leu505 to His substitution (BRAF L505H ), is the first resistance-conferring second-site mutation identified in BRAF mutant cells. The mutation replaces a small nonpolar amino acid at the BRAF-PLX4032 interface with a larger polar residue. Moreover, we show that BRAF L505H , found in human prostate cancer, is itself a MAPK-activating, PLX4032-resistant oncogenic mutation. Lastly, we demonstrate that the PLX4032-resistant melanoma cells are sensitive to novel, next-generation BRAF inhibitors, especially the 'paradox-blocker' PLX8394, supporting its use in clinical trials for treatment of melanoma patients with BRAF-mutations.

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KW - Paradox blockers

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