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Cancer Discovery
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Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations

Leanne G. Ahronian, Erin M. Sennott, Eliezer M. Van Allen, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, Jason T. Godfrey, Koki Nishimura, Kerry D. Lynch, Craig H. Mermel, Elizabeth L. Lockerman, Anuj Kalsy, Joseph M. Gurski Jr, Samira Bahl, Kristin Anderka, Lisa M. Green, Niall J. Lennon, Tiffany G. Huynh, Mari Mino-Kenudson, Gad Getz, Dora Dias-Santagata, A. John Iafrate, Jeffrey A. Engelman, Levi A. Garraway and Ryan B. Corcoran
Leanne G. Ahronian
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Erin M. Sennott
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Eliezer M. Van Allen
3Dana Farber Cancer Institute, Boston, Massachusetts.
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Nikhil Wagle
3Dana Farber Cancer Institute, Boston, Massachusetts.
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Eunice L. Kwak
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Jason E. Faris
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Jason T. Godfrey
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
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Koki Nishimura
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
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Kerry D. Lynch
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Craig H. Mermel
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Elizabeth L. Lockerman
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
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Anuj Kalsy
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
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Joseph M. Gurski Jr
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Samira Bahl
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Kristin Anderka
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Lisa M. Green
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Niall J. Lennon
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Tiffany G. Huynh
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Mari Mino-Kenudson
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Gad Getz
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Dora Dias-Santagata
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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A. John Iafrate
5Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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Jeffrey A. Engelman
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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Levi A. Garraway
3Dana Farber Cancer Institute, Boston, Massachusetts.
4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
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Ryan B. Corcoran
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2Department of Medicine, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: rbcorcoran@partners.org
DOI: 10.1158/2159-8290.CD-14-1518 Published April 2015
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Abstract

BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance. To identify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorectal cancer treated with RAF inhibitor combinations. We identified alterations in MAPK pathway genes in resistant tumors not present in matched pretreatment tumors, including KRAS amplification, BRAF amplification, and a MEK1 mutation. These alterations conferred resistance to RAF/EGFR or RAF/MEK combinations through sustained MAPK pathway activity, but an ERK inhibitor could suppress MAPK activity and overcome resistance. Identification of MAPK pathway reactivating alterations upon clinical acquired resistance underscores the MAPK pathway as a critical target in BRAF-mutant colorectal cancer and suggests therapeutic options to overcome resistance.

Significance: RAF inhibitor combinations represent promising approaches in clinical development for BRAF-mutant colorectal cancer. Initial characterization of clinical acquired resistance mechanisms to these regimens identified several MAPK pathway alterations driving resistance by reactivating MAPK signaling, highlighting the critical dependence of BRAF-mutant colorectal cancers on MAPK signaling and offering potential strategies to overcome resistance. Cancer Discov; 5(4); 358–67. ©2015 AACR.

See related commentary by Meador and Pao, p. 348

This article is highlighted in the In This Issue feature, p. 333

Footnotes

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

  • Received December 22, 2014.
  • Revision received January 27, 2015.
  • Accepted February 2, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Discovery: 5 (4)
April 2015
Volume 5, Issue 4
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Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations
Leanne G. Ahronian, Erin M. Sennott, Eliezer M. Van Allen, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, Jason T. Godfrey, Koki Nishimura, Kerry D. Lynch, Craig H. Mermel, Elizabeth L. Lockerman, Anuj Kalsy, Joseph M. Gurski Jr, Samira Bahl, Kristin Anderka, Lisa M. Green, Niall J. Lennon, Tiffany G. Huynh, Mari Mino-Kenudson, Gad Getz, Dora Dias-Santagata, A. John Iafrate, Jeffrey A. Engelman, Levi A. Garraway and Ryan B. Corcoran
Cancer Discov April 1 2015 (5) (4) 358-367; DOI: 10.1158/2159-8290.CD-14-1518

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Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations
Leanne G. Ahronian, Erin M. Sennott, Eliezer M. Van Allen, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, Jason T. Godfrey, Koki Nishimura, Kerry D. Lynch, Craig H. Mermel, Elizabeth L. Lockerman, Anuj Kalsy, Joseph M. Gurski Jr, Samira Bahl, Kristin Anderka, Lisa M. Green, Niall J. Lennon, Tiffany G. Huynh, Mari Mino-Kenudson, Gad Getz, Dora Dias-Santagata, A. John Iafrate, Jeffrey A. Engelman, Levi A. Garraway and Ryan B. Corcoran
Cancer Discov April 1 2015 (5) (4) 358-367; DOI: 10.1158/2159-8290.CD-14-1518
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