Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma

doi:10.1016/j.cytogfr.2019.12.005

Cytokine & Growth Factor Reviews

Volume 52, April 2020, Pages 56-67

https://doi.org/10.1016/j.cytogfr.2019.12.005 Get rights and content

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open access

Highlights

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Intrahepatic cholangiocarcinoma (ICC), a subset of primary liver cancer, is one of the most lethal cancers with very limited treatment options.
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Aberrant activation of a number of molecular pathways drives ICC pathogenesis.
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Chromosomal translocations with Fibroblast Growth Factor Receptor 2 (FGFR2) – a Receptor Tyrosine Kinase – have been identified as drivers in ICC.
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Structural comparisons of FGFR2 translocations and molecular signaling pathways are presented, together with therapeutic approaches.
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This review presents the unifying features of oncogenic FGFR2 translocations and the current landscape of TKIs in clinical trials for ICC patients.

Abstract

Cholangiocarcinoma, originating from the biliary duct, represents a subset of liver cancer. With about 8000 new cases of cholangiocarcinoma diagnosed annually in the U.S., these fall into three categories: intrahepatic, peri-hilar, and extrahepatic cholangiocarcinoma. Arising from the epithelium of the bile duct, intrahepatic cholangiocarcinoma (ICC) is a universally fatal malignancy with very few treatment options. The poor prognosis and lack of molecular targeted therapies highlights ICC as a critical unmet medical need. With advances in sequencing technology, numerous chromosomal translocations have been discovered as drivers in cancer initiation and progression. Particularly in ICC, chromosomal translocations involving Fibroblast Growth Factor Receptor 2 (FGFR2) have been frequently identified, resulting in the creation of oncogenic fusion proteins. At the N-terminus, these fusion proteins share a nearly-identical FGFR2 moiety retaining an intact kinase domain and, at the C-terminus, a dimerization/oligomerization domain provided by different partner genes, including: Periphilin 1 (PPHLN1), Bicaudal family RNA binding protein 1 (BICC1), Adenosylhomocysteinase Like 1 (AHCYL1), and Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3). A number of pre-clinical and clinical trials have shown the effectiveness of FGFR inhibitors in treating FGFR2 fusion-positive ICC patients. However, the efficacy of these inhibitors may be short-lived due to acquired resistance. In this review, we provide an overview of FGFR2 fusions, comparing their structures and mechanism of dimerization, examining the importance of FGFR2 as a partner gene, as well as highlighting the significance of alternative splicing of FGFR2 in these fusion proteins. In addition, we discuss various therapeutic options and their associated potencies in targeting these translocation-induced ICCs.

Keywords

Oncogenic fusion protein

Chromosomal translocation

RTK

Liver cancer

Fibroblast growth factor receptor

Bile duct cancer

Cited by (0)

Fangda Li recently completed a Master’s degree in the Donoghue group in the Department of Chemistry and Biochemistry at the University of California, San Diego. He is currently a doctoral student at Columbia University Irving Medical Center. He earned his B.A. in biological chemistry from Grinnell College. His research focuses on identifying and characterizing novel oncogenic signaling mechanisms and interactions, specifically in the FGFR pathway.

Malalage Nicole Peiris is a graduate student researcher in the Donoghue group in the Department of Chemistry & Biochemistry at the University of California, San Diego. She obtained her Bachelor’s degree in Biochemistry and Molecular Biology from the University of California, Davis. She is currently in her fifth year of her doctoral thesis studying the activation of FGFR1 fusions in hematopoietic cancers.

Daniel J. Donoghue is a Professor in the Department of Chemistry & Biochemistry at UC San Diego. He received his graduate training with Phillip A. Sharp at MIT, and postdoctoral training with Tony Hunter at the Salk Institute before joining UC San Diego. He has a lifelong interest in Receptor Tyrosine Kinases and their roles in human cancer.