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Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma

Melanie A. Krook, Alexandria Lenyo, Max Wilberding, Hannah Barker, Mikayla Dantuono, Kelly M. Bailey, Hui-Zi Chen, Julie W. Reeser, Michele R. Wing, Jharna Miya, Eric Samorodnitsky, Amy M. Smith, Thuy Dao, Dorrelyn M. Martin, Kristen K. Ciombor, John Hays, Aharon G. Freud and Sameek Roychowdhury
Melanie A. Krook
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Alexandria Lenyo
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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  • ORCID record for Alexandria Lenyo
Max Wilberding
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Hannah Barker
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Mikayla Dantuono
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Kelly M. Bailey
2Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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Hui-Zi Chen
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
3Department of Internal Medicine, Hematology and Oncology Fellowship Program, The Ohio State University, Columbus, Ohio.
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Julie W. Reeser
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Michele R. Wing
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Jharna Miya
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Eric Samorodnitsky
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Amy M. Smith
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Thuy Dao
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Dorrelyn M. Martin
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Kristen K. Ciombor
4Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
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John Hays
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
5Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
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Aharon G. Freud
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
6Department of Pathology, The Ohio State University, Columbus, Ohio.
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Sameek Roychowdhury
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
5Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
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  • For correspondence: sameek.roychowdhury@osumc.edu
DOI: 10.1158/1535-7163.MCT-19-0631 Published March 2020
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Abstract

The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro. Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.

This article is featured in Highlights of This Issue, p. 729

Footnotes

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

  • Mol Cancer Ther 2020;19:847–57

  • Received June 25, 2019.
  • Revision received October 15, 2019.
  • Accepted December 19, 2019.
  • Published first January 7, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (3)
March 2020
Volume 19, Issue 3
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Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma
Melanie A. Krook, Alexandria Lenyo, Max Wilberding, Hannah Barker, Mikayla Dantuono, Kelly M. Bailey, Hui-Zi Chen, Julie W. Reeser, Michele R. Wing, Jharna Miya, Eric Samorodnitsky, Amy M. Smith, Thuy Dao, Dorrelyn M. Martin, Kristen K. Ciombor, John Hays, Aharon G. Freud and Sameek Roychowdhury
Mol Cancer Ther March 1 2020 (19) (3) 847-857; DOI: 10.1158/1535-7163.MCT-19-0631

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Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma
Melanie A. Krook, Alexandria Lenyo, Max Wilberding, Hannah Barker, Mikayla Dantuono, Kelly M. Bailey, Hui-Zi Chen, Julie W. Reeser, Michele R. Wing, Jharna Miya, Eric Samorodnitsky, Amy M. Smith, Thuy Dao, Dorrelyn M. Martin, Kristen K. Ciombor, John Hays, Aharon G. Freud and Sameek Roychowdhury
Mol Cancer Ther March 1 2020 (19) (3) 847-857; DOI: 10.1158/1535-7163.MCT-19-0631
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