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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Signal Transduction

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

Thomas C. Beadnell, Katie M. Mishall, Qiong Zhou, Stephen M. Riffert, Kelsey E. Wuensch, Brittelle E. Kessler, Maia L. Corpuz, Xia Jing, Jihye Kim, Guoliang Wang, Aik Choon Tan and Rebecca E. Schweppe
Thomas C. Beadnell
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Katie M. Mishall
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Qiong Zhou
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Stephen M. Riffert
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Kelsey E. Wuensch
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Brittelle E. Kessler
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Maia L. Corpuz
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Xia Jing
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Jihye Kim
2Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Guoliang Wang
2Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
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Aik Choon Tan
2Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
3University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado.
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Rebecca E. Schweppe
1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
3University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado.
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  • For correspondence: Rebecca.Schweppe@ucdenver.edu
DOI: 10.1158/1535-7163.MCT-15-0702 Published August 2016
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Abstract

Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor dasatinib. Upon acquisition of dasatinib resistance, the two RAS-mutant cell lines acquired the c-SRC gatekeeper mutation (T341M), whereas the two BRAF-mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinib-resistant cell lines. Interestingly, activation of the MAPK pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcame acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling play important roles in promoting resistance to the Src inhibitor dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. Mol Cancer Ther; 15(8); 1952–63. ©2016 AACR.

Footnotes

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

  • Received August 21, 2015.
  • Revision received May 9, 2016.
  • Accepted May 11, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 15 (8)
August 2016
Volume 15, Issue 8
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The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer
Thomas C. Beadnell, Katie M. Mishall, Qiong Zhou, Stephen M. Riffert, Kelsey E. Wuensch, Brittelle E. Kessler, Maia L. Corpuz, Xia Jing, Jihye Kim, Guoliang Wang, Aik Choon Tan and Rebecca E. Schweppe
Mol Cancer Ther August 1 2016 (15) (8) 1952-1963; DOI: 10.1158/1535-7163.MCT-15-0702

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The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer
Thomas C. Beadnell, Katie M. Mishall, Qiong Zhou, Stephen M. Riffert, Kelsey E. Wuensch, Brittelle E. Kessler, Maia L. Corpuz, Xia Jing, Jihye Kim, Guoliang Wang, Aik Choon Tan and Rebecca E. Schweppe
Mol Cancer Ther August 1 2016 (15) (8) 1952-1963; DOI: 10.1158/1535-7163.MCT-15-0702
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