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Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors

Hubing Shi, Gatien Moriceau, Xiangju Kong, Richard C. Koya, Ramin Nazarian, Gulietta M. Pupo, Antonella Bacchiocchi, Kimberly B. Dahlman, Bartosz Chmielowski, Jeffrey A. Sosman, Ruth Halaban, Richard F. Kefford, Georgina V. Long, Antoni Ribas and Roger S. Lo
Hubing Shi
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Gatien Moriceau
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Xiangju Kong
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Richard C. Koya
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Ramin Nazarian
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Gulietta M. Pupo
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Antonella Bacchiocchi
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Kimberly B. Dahlman
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Bartosz Chmielowski
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Jeffrey A. Sosman
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Ruth Halaban
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Richard F. Kefford
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Georgina V. Long
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Antoni Ribas
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Roger S. Lo
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DOI: 10.1158/2159-8290.CD-12-0022 Published May 2012
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Abstract

BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for by BRAFi. We sequenced MEK1/2 exon 3 in melanomas at baseline and upon disease progression. Of 31 baseline V600E/KBRAF melanomas, 5 (16%) carried concurrent somatic BRAF/MEK1 activating mutations. Three of 5 patients with BRAF/MEK1 double-mutant baseline melanomas showed objective tumor responses, consistent with the overall 60% frequency. No MEK1 mutation was found in disease progression melanomas, except when it was already identified at baseline. MEK1-mutant expression in V600E/KBRAF melanoma cell lines resulted in no significant alterations in p-ERK1/2 levels or growth-inhibitory sensitivities to BRAFi, MEK1/2 inhibitor (MEKi), or their combination. Thus, activating MEK1 exon 3 mutations identified herein and concurrent with V600E/KBRAF do not cause BRAFi resistance in melanoma. Cancer Discov; 2(5); 414–24. ©2012 AACR.

Significance: As BRAF inhibitors gain widespread use for treatment of advanced melanoma, biomarkers for drug sensitivity or resistance are urgently needed. We identify here concurrent activating mutations in BRAF and MEK1 in melanomas and show that the presence of a downstream mutation in MEK1 does not necessarily make BRAF–mutant melanomas resistant to BRAF inhibitors.

Read the Commentary on this article by Paraiso and Smalley, p. 390.

This article is highlighted in the In This Issue feature, p. 377.

Footnotes

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

  • Received January 18, 2012.
  • Revision received March 1, 2012.
  • Accepted March 6, 2012.
  • ©2012 American Association for Cancer Research.

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Cancer Discovery: 2 (5)
May 2012
Volume 2, Issue 5
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Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Hubing Shi, Gatien Moriceau, Xiangju Kong, Richard C. Koya, Ramin Nazarian, Gulietta M. Pupo, Antonella Bacchiocchi, Kimberly B. Dahlman, Bartosz Chmielowski, Jeffrey A. Sosman, Ruth Halaban, Richard F. Kefford, Georgina V. Long, Antoni Ribas and Roger S. Lo
Cancer Discov May 1 2012 (2) (5) 414-424; DOI: 10.1158/2159-8290.CD-12-0022

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Preexisting MEK1 Exon 3 Mutations in V600E/KBRAF Melanomas Do Not Confer Resistance to BRAF Inhibitors
Hubing Shi, Gatien Moriceau, Xiangju Kong, Richard C. Koya, Ramin Nazarian, Gulietta M. Pupo, Antonella Bacchiocchi, Kimberly B. Dahlman, Bartosz Chmielowski, Jeffrey A. Sosman, Ruth Halaban, Richard F. Kefford, Georgina V. Long, Antoni Ribas and Roger S. Lo
Cancer Discov May 1 2012 (2) (5) 414-424; DOI: 10.1158/2159-8290.CD-12-0022
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