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

doi:10.1111/pcmr.12197

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

Dermatology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	253-262
Number of pages	10
Journal	Pigment Cell and Melanoma Research
Volume	27
Issue number	2
DOIs	https://doi.org/10.1111/pcmr.12197
State	Published - Mar 2014

Keywords

BRAF
Drug resistance
Melanoma
PLX4032
Paradox blockers

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology
Dermatology
Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/pcmr.12197

Cite this

Choi, J., Landrette, S. F., Wang, T., Evans, P., Bacchiocchi, A., Bjornson, R., Cheng, E., Stiegler, A. L., Gathiaka, S., Acevedo, O., Boggon, T. J., Krauthammer, M., Halaban, 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

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title = "Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors",

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 BRAFV600K 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 (BRAFL505H), 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 BRAFL505H, 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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doi = "10.1111/pcmr.12197",

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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

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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 BRAFV600K 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 (BRAFL505H), 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 BRAFL505H, 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 BRAFV600K 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 (BRAFL505H), 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 BRAFL505H, 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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Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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