Case report: FGFR2 inhibitor resistance via PIK3CA and CDKN2A/B in an intrahepatic cholangiocarcinoma patient with FGFR2-SH3GLB1 fusion

Nadja Ballin ^1* Alexander Ott ¹ Olga Seibel-Kelemen ¹ Irina Bonzheim ² Dominik Nann ² Janina Beha ³ Stephan Spahn ⁴ Stephan Singer ² Stephan Ossowski ¹ Cristiana Roggia ¹ Christopher Schroeder ¹ Michael Bitzer ^3,4 Sorin Armeanu-Ebinger ¹

• ¹ Institute of Medical Genetics and Applied Genomics, University Hospital and Faculty of Medicine, University of Tübingen, Tuebingen, Germany
• ² Department of Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany, Tübingen, Germany
• ³ Center for Personalized Medicine, University Hospital Tübingen, Tübingen, Germany, Tübingen, Germany
• ⁴ Department of Internal Medicine I, University Hospital Tübingen, Tübingen, Germany, Tübingen, Germany

FGFR2 fusions occur in up to 14% of patients with intrahepatic cholangiocarcinoma (iCCA) and have been considered as therapeutic target for FGFR inhibitors (FGFRi). However, response to targeted treatment may be limited due to the emergence of various resistance mechanisms. We report a case of recurrent iCCA in a 43-year-old patient with a FGFR2 fusion, who was treated with Lenvatinib. Nextgeneration sequencing (NGS) of tumor-normal DNA and tumor RNA under Lenvatinib treatment confirmed the FGFR2 fusion, however no further molecular resistance mutation was observed. After failure of FGFRi treatment (Lenvatinib and Infigratinib) ten months later, repeated NGS analysis revealed a new gain-of-function mutation in PIK3CA and a homozygous deletion of CDKN2A/B, potentially representing an acquired resistance mechanism. The emerging acquired resistance to FGFR inhibitor treatment has implications for subsequent treatment strategies.