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Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):13456-13461. Epub 2016 Nov 9.

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF-mutant lung cancer.

Okimoto RA1,2,3, Lin L1,2, Olivas V1,2,3, Chan E1,2,3, Markegard E2, Rymar A4, Neel D1,2,3, Chen X1,2, Hemmati G1,2,3, Bollag G4, Bivona TG5,2,3.

Author information

Department of Medicine, University of California, San Francisco, CA 94158.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158.
Plexxikon Inc., Berkeley, CA 94710.
Department of Medicine, University of California, San Francisco, CA 94158;


Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAFV600E-mutant allele, the spectrum of BRAF mutations in LA includes BRAFV600E (∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAFG469A and BRAFG466V The presence of BRAFV600E in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAFV600E-mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAFV600E and certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAFV600E that promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.


BRAF; cancer; lung; targeted therapy

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

G.B. and A.R. are employees of Plexxikon, Inc., which produced vemurafenib and PLX8394. T.G.B. is a consultant to Driver Group, Novartis, Astellas, Natera, Array Biopharma, Ariad, Teva, Astrazeneca, and a recipient of research grants from Servier and Ignyta.

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