Reference Detail

Ref Type

Journal Article

PMID

(27834212)

Authors

Okimoto RA, Lin L, Olivas V, Chan E, Markegard E, Rymar A, Neel D, Chen X, Hemmati G, Bollag G, Bivona TG

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America	113	47	2016 11 22	13456-13461	Proc Natl Acad Sci U S A

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF G466V	lung adenocarcinoma	sensitive	PLX8394	Preclinical - Cell culture	Actionable	In a preclinical study, PLX8394 decreased growth of lung adenocarcinoma cell lines harboring BRAF G466V in culture (PMID: 27834212).	27834212
BRAF G469A	lung adenocarcinoma	sensitive	PLX8394	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PLX8394 decreased growth of lung adenocarcinoma cell lines harboring BRAF G469A in culture, and reduced tumor growth in xenograft models (PMID: 27834212).	27834212