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Research Brief

V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer

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 and Rona Yaeger
Yijun Gao
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ann Maria
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Na Na
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Arnaud da Cruz Paula
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Alexander N. Gorelick
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jaclyn F. Hechtman
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Julianne Carson
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Robert A. Lefkowitz
Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Britta Weigelt
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Barry S. Taylor
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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HuiYong Zhao
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jorge S. Reis-Filho
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Elisa de Stanchina
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Neal Rosen
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Neal Rosen
Zhan Yao
Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Rona Yaeger
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: yaegerr@mskcc.org
DOI: 10.1158/2159-8290.CD-19-0356 Published September 2019
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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.

Significance: 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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2019;9:1182–91

  • Received March 20, 2019.
  • Revision received June 10, 2019.
  • Accepted June 18, 2019.
  • Published first June 21, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (9)
September 2019
Volume 9, Issue 9
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V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer
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 and Rona Yaeger
Cancer Discov September 1 2019 (9) (9) 1182-1191; DOI: 10.1158/2159-8290.CD-19-0356

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V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer
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 and Rona Yaeger
Cancer Discov September 1 2019 (9) (9) 1182-1191; DOI: 10.1158/2159-8290.CD-19-0356
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