期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：13456-13461
DOI：10.1073/pnas.1610456113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceOncogenic mutations in the BRAF protein kinase occur in a large number of patients with lung cancer, the number one cause of cancer mortality worldwide. Despite the relatively high frequency (2-7%) of various oncogenic BRAF alleles in human lung adenocarcinoma (LA), the biological and clinical relevance of these mutations and the optimal therapeutic strategy to improve outcomes remains poorly defined. We report the preclinical efficacy of a next-generation BRAF kinase inhibitor across a spectrum of clinically relevant BRAF-mutant nonsmall cell lung cancer (NSCLC) models. Our results provide biological insight into the regulation of BRAF oncogene dependence and identify strategies to improve outcomes in patients with BRAF-mutant lung cancer. 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.
