Preexisting MEK1 Exon 3 Mutations in V600E/K BRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Autor: | Antonella Bacchiocchi, Roger S. Lo, Richard F. Kefford, Georgina V. Long, Gulietta M. Pupo, Richard C. Koya, Jeffrey A. Sosman, Ramin Nazarian, Hubing Shi, Gatien Moriceau, Ruth Halaban, Antoni Ribas, Bartosz Chmielowski, Kimberly B. Dahlman, Xiangju Kong |
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Rok vydání: | 2012 |
Předmět: |
Male
Proto-Oncogene Proteins B-raf endocrine system diseases Somatic cell MAP Kinase Kinase 1 Drug resistance Biology Bioinformatics medicine.disease_cause Article Exon medicine Humans Vemurafenib Melanoma neoplasms Mutation Cancer medicine.disease digestive system diseases Oncology Drug Resistance Neoplasm Cancer research Female V600E medicine.drug |
Zdroj: | Cancer Discovery. 2:414-424 |
ISSN: | 2159-8290 2159-8274 |
Popis: | BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression. Of 31 baseline V600E/KBRAF melanomas, 5 (16%) carried concurrent somatic BRAF/MEK1 activating mutations. Three of 5 patients with BRAF/MEK1 double-mutant baseline melanomas showed objective tumor responses, consistent with the overall 60% frequency. No MEK1 mutation was found in disease progression melanomas, except when it was already identified at baseline. MEK1-mutant expression in V600E/KBRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor (MEKi), or their combination. Thus, activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAFi resistance in melanoma. Cancer Discov; 2(5); 414–24. ©2012 AACR. Significance: As BRAF inhibitors gain widespread use for treatment of advanced melanoma, biomarkers for drug sensitivity or resistance are urgently needed. We identify here concurrent activating mutations in BRAF and MEK1 in melanomas and show that the presence of a downstream mutation in MEK1 does not necessarily make BRAF–mutant melanomas resistant to BRAF inhibitors. Read the Commentary on this article by Paraiso and Smalley, p. 390. This article is highlighted in the In This Issue feature, p. 377. |
Databáze: | OpenAIRE |
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