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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Research Article

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

The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15-20% of intrahepatic cholangiocarcinoma patients. 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 eight 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 (SNVs) 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.

  • Received June 25, 2019.
  • Revision received October 15, 2019.
  • Accepted December 19, 2019.
  • Copyright ©2020, American Association for Cancer Research.
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This OnlineFirst version was published on January 7, 2020
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 January 7 2020 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 January 7 2020 DOI: 10.1158/1535-7163.MCT-19-0631
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Molecular Cancer Therapeutics
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