American Association for Cancer Research
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Supplementary Data from V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer

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posted on 2023-04-03, 22:48 authored by Yijun Gao, Ann Maria, Na Na, Arnaud da Cruz Paula, Alexander N. Gorelick, Jaclyn F. Hechtman, Julianne Carson, Robert A. Lefkowitz, Britta Weigelt, Barry S. Taylor, HuiYong Zhao, Jorge S. Reis-Filho, Elisa de Stanchina, Neal Rosen, Zhan Yao, Rona Yaeger

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Byrne Fund

Sarah Jenkins Fund

Breast Cancer Research Foundation

NIH

Cancer Center Core

Stand Up To Cancer

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ARTICLE ABSTRACT

We report the emergence of the novel MEK1V211D gatekeeper mutation in a patient with BRAFK601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1V211D mutation concurrently occurs in the same cell with BRAFK601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance. We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A MEK1V211D mutation developed in a patient with BRAFK601E colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors.This article is highlighted in the In This Issue feature, p. 1143

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