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Abstract A289: Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation.

2013; American Association for Cancer Research; Volume: 12; Issue: 11_Supplement Linguagem: Inglês

10.1158/1535-7163.targ-13-a289

1538-8514

Yusuke Narita, Kiyoshi Okamoto, Megumi Ikemori Kawada, Kazuma Takase, Yukinori Minoshima, Kotaro Kodama, Masao Iwata,

Cancer Mechanisms and Therapy

Abstract Many clinical cases of acquired resistance to the BRAF inhibitor vemurafenib have recently been reported. One of the causes of this acquired resistance is the BRAF downstream kinase point mutation MEK1-C121S. This mutation confers resistance to not only vemurafenib, but also to the allosteric MEK inhibitor selumetinib (AZD6244). Here, we investigated the pharmacological activities and effectiveness of the novel MEK inhibitor E6201 against BRAF-V600E mutant melanoma harboring the MEK1-C121S mutation. A cell-free assay confirmed that E6201 is an ATP-competitive MEK inhibitor meaning it has a different binding mode with MEK compared with allosteric MEK inhibitors. E6201 is more effective against BRAF-V600E mutant melanoma compared with BRAF wild-type melanoma based on MEK inhibition. We found that the acquired MEK1-C121S mutation in BRAF-V600E mutant melanoma conferred resistance to both vemurafenib and selumetinib but not E6201. The effectiveness of E6201 is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable influence the MAPK pathway inhibitory activity. We conclude that E6201 is a potential therapeutic choice for improving the clinical outcome of vemurafenib-based therapy. However, further validation is needed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A289. Citation Format: Yusuke Narita, Kiyoshi Okamoto, Megumi Ikemori Kawada, Kazuma Takase, Yukinori Minoshima, Kotaro Kodama, Masao Iwata. Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A289.