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BRAF-inhibitor associated MEK mutations increase RAF-dependent and -independent enzymatic activity

Emery, Caroline, Monaco, Kelli-Ann, Wang, Ping, Balak, Marissa, Freeman, Alyson, Meltzer, Jodi, Delach, Scott, Rakiec, Daniel, Ruddy, David, Korn, Joshua, Haling, Jake, Acker, Michael and Caponigro, Giordano (2017) BRAF-inhibitor associated MEK mutations increase RAF-dependent and -independent enzymatic activity. Molecular Cancer Research, 15 (10). pp. 1431-1444. ISSN 1557-3125


Alterations in MEK1/2 occur in cancers, both in the treatment-naïve state and following targeted therapies, most notably BRAF and MEK inhibitors in BRAF-V600E–mutant melanoma and colorectal cancer. Efforts were undertaken to understand the effects of these mutations, based upon protein structural location, and MEK1/2 activity. Two categories of MEK1/2 alterations were evaluated, those associated with either the allosteric pocket or helix-A. Clinically, MEK1/2 alterations of the allosteric pocket are rare and we demonstrate that they confer resistance to MEK inhibitors, while retaining sensitivity to BRAF inhibition. Most mutations described in patients fall within, or are associated with, helix-A. Mutations in this region reduce sensitivity to both BRAF and MEK inhibition and display elevated phospho-ERK1/2 levels, independent from increases in phospho-MEK1/2. Biochemical experiments with a representative helix-A variant, MEK1-Q56P, reveal both increased catalytic efficiency of the activated enzyme, and phosphorylation-independent activity relative to wild-type MEK1. Consistent with these findings, MEK1/2 alterations in helix A retain sensitivity to downstream antagonism via pharmacologic inhibition of ERK1/2. This work highlights the importance of classifying mutations based on structural and phenotypic consequences, both in terms of pathway signaling output and response to pharmacologic inhibition.

Item Type: Article
Date Deposited: 10 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45


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