Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer
| العنوان: | Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer |
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| المؤلفون: | Elton Chan, Evan Markegard, Ross A. Okimoto, Luping Lin, Trever G. Bivona, Andrey Rymar, Victor Olivas, Xiao Chen, Dana S. Neel, Golzar Hemmati, Gideon Bollag |
| المصدر: | Proceedings of the National Academy of Sciences. 113:13456-13461 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Proto-Oncogene Proteins B-raf, 0301 basic medicine, MAPK/ERK pathway, Lung Neoplasms, endocrine system diseases, Combination therapy, MAP Kinase Signaling System, Antineoplastic Agents, Mice, SCID, Mechanistic Target of Rapamycin Complex 1, Biology, Heterocyclic Compounds, 2-Ring, Proto-Oncogene Mas, 03 medical and health sciences, 0302 clinical medicine, In vivo, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, skin and connective tissue diseases, Vemurafenib, Protein kinase A, Lung cancer, neoplasms, Protein Kinase Inhibitors, Sulfonamides, Multidisciplinary, Biological Sciences, medicine.disease, digestive system diseases, Enzyme Activation, Treatment Outcome, 030104 developmental biology, Drug Resistance, Neoplasm, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Mutation, Cancer research, Adenocarcinoma, Female, V600E, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e03b1430541355f9bf381c936f725c75 https://doi.org/10.1073/pnas.1610456113 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e03b1430541355f9bf381c936f725c75 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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