Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma

Authors

Bitzer M^{1 2 3 4}, Spahn S⁵, Babaei S⁵, Horger M⁶, Singer S⁷, Schulze-Osthoff K^{8 9 10}, Missios P⁵, Gatidis S⁶, Nann D⁷, Mattern S⁷, Scheble V⁵, Nikolaou K⁶, Armeanu-Ebinger S¹¹, Schulze M¹², Schroeder C¹¹, Biskup S¹², Beha J¹³, Claassen M⁵, Ruhm K¹³, Poso A^{8 9 14}, Malek NP^{5 13 8 9}

Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany. michael.bitzer@med.uni-tuebingen.de.
Center for Personalized Medicine, Eberhard-Karls University, Tübingen, Germany. michael.bitzer@med.uni-tuebingen.de.
Cluster of Excellence, Image Guided and Functionally Instructed Tumor Therapies, Eberhard-Karls University, Tübingen, Germany. michael.bitzer@med.uni-tuebingen.de.
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. michael.bitzer@med.uni-tuebingen.de.
Department of Internal Medicine I, Eberhard-Karls University, Tübingen, Germany.
Department of Diagnostic and Interventional Radiology, Eberhard-Karls University, Tübingen, Germany.
Institute of Pathology and Neuropathology, Eberhard-Karls University, Tübingen, Germany.
Cluster of Excellence, Image Guided and Functionally Instructed Tumor Therapies, Eberhard-Karls University, Tübingen, Germany.
German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard-Karls University, Tübingen, Germany.
Institute of Medical Genetics and Applied Genomics, Eberhard-Karls University, Tübingen, Germany.
CeGaT GmbH and Praxis für Humangenetik, Tübingen, Germany.
Center for Personalized Medicine, Eberhard-Karls University, Tübingen, Germany.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.