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 pharmacologic activities and effectiveness of the novel MEK inhibitor E6201 against BRAF (v-raf murine sarcoma viral oncogene homolog B1)-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 in this preclinical study is a result of its binding with MEK1 far from the C121S point mutation so the mutation is unable to influence the MAPK pathway inhibitory activity. These results support further clinical investigation of E6201.
Highlights
In certain types of cancer, the activation of kinases is known to have a role in oncogenicity [1]
The inhibitory activity of E6201 in the MEK1-C121S transfectants was the same as that in the MEK1-WT transfectants. These results indicate that vemurafenib and selumetinib resistance and the effectiveness of E6201 against MEK1-C121S mutant melanoma is caused by inhibition of the mitogenactivated protein kinase (MAPK) pathway
We showed that E6201 is effective in a preclinical model against BRAF-V600E melanoma harboring the MEK1-C121S mutation
Summary
In certain types of cancer, the activation of kinases is known to have a role in oncogenicity [1]. Kinase inhibitors are an attractive option for use as cancer chemotherapy [2]. These drugs confer a survival benefit to patients with cancer; a number of mechanisms of acquired resistance to kinase inhibitors have been reported [3, 4]. Gatekeeper mutations that confer resistance to kinase inhibitors frequently occur in EGFR [5, 6] and BCR-ABL [7]. A clinical trial showed that the BRAF inhibitor vemurafenib conferred significant survival benefit in patients with melanomas harboring BRAF-V600E, and vemurafenib has since been approved by both the U.S Food and Drug
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