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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Cancer Biology and Translational Studies

ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms

Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D. Hintzsche, Anh Le, Todd M. Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C. Doebele and William A. Robinson
Kasey L. Couts
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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  • For correspondence: kasey.couts@ucdenver.edu
Judson Bemis
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Jacqueline A. Turner
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Stacey M. Bagby
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Danielle Murphy
Ignyta, Inc, San Diego, California.
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Jason Christiansen
Ignyta, Inc, San Diego, California.
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Jennifer D. Hintzsche
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Anh Le
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Todd M. Pitts
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Keith Wells
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Allison Applegate
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Carol Amato
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Pratik Multani
Ignyta, Inc, San Diego, California.
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Edna Chow-Maneval
Ignyta, Inc, San Diego, California.
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John J. Tentler
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Yiqun G. Shellman
Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Matthew J. Rioth
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Aik-Choon Tan
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Rene Gonzalez
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Theresa Medina
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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Robert C. Doebele
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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William A. Robinson
Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
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DOI: 10.1158/1535-7163.MCT-17-0472 Published January 2018
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Abstract

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALKATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALKATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALKATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALKATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALKATI. Mol Cancer Ther; 17(1); 222–31. ©2017 AACR.

This article is featured in Highlights of This Issue, p. 1

Footnotes

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

  • Received May 22, 2017.
  • Revision received August 25, 2017.
  • Accepted September 28, 2017.
  • ©2017 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 17 (1)
January 2018
Volume 17, Issue 1
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ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms
Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D. Hintzsche, Anh Le, Todd M. Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C. Doebele and William A. Robinson
Mol Cancer Ther January 1 2018 (17) (1) 222-231; DOI: 10.1158/1535-7163.MCT-17-0472

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ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms
Kasey L. Couts, Judson Bemis, Jacqueline A. Turner, Stacey M. Bagby, Danielle Murphy, Jason Christiansen, Jennifer D. Hintzsche, Anh Le, Todd M. Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J. Tentler, Yiqun G. Shellman, Matthew J. Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C. Doebele and William A. Robinson
Mol Cancer Ther January 1 2018 (17) (1) 222-231; DOI: 10.1158/1535-7163.MCT-17-0472
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