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Targeting FGFR inhibition in cholangiocarcinoma

Goyal, L; Kongpetch, S; Crolley, VE; Bridgewater, J; (2021) Targeting FGFR inhibition in cholangiocarcinoma. Cancer Treatment Reviews , 95 , Article 102170. 10.1016/j.ctrv.2021.102170. Green open access

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Abstract

Cholangiocarcinomas (CCAs) are rare but aggressive tumours of the bile ducts, which are often diagnosed at an advanced stage and have poor outcomes on systemic therapy. Somatic alterations with therapeutic implications have been identified in almost half of CCAs, in particular in intrahepatic CCA (iCCA), the subtype arising from bile ducts within the liver. Among patients with CCA, fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements occur almost exclusively in iCCA, where they are estimated to be found in up to 10–15% of patients. Clinical trials for selective FGFR kinase inhibitors have shown consistent activity of these agents in previously treated patients with iCCA harbouring FGFR alterations. Current FGFR kinase inhibitors show differences in their structure, mechanisms of target engagement, and specificities for FGFR1, 2, 3 and 4 and other related kinases. These agents offer the potential to improve outcomes in FGFR-driven CCA, and the impact of variations in the molecular profiles of the FGFR inhibitors on efficacy, safety, acquired resistance mechanisms, and patients’ health-related quality of life remains to be fully characterized. The most common adverse event associated with FGFR inhibitors is hyperphosphatemia, an on-target off-tumour effect of FGFR1 inhibition, and strategies to manage this include dose adjustment, chelators, and the use of a low phosphate diet. As FGFR inhibitors and other targeted agents enter the clinic for use in FGFR-driven CCA, molecular testing for actionable mutations and monitoring for the emergence of acquired resistance will be essential.

Type: Article
Title: Targeting FGFR inhibition in cholangiocarcinoma
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ctrv.2021.102170
Publisher version: http://doi.org/10.1016/j.ctrv.2021.102170
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cholangiocarcinoma; Receptor, Fibroblast Growth Factor, Type 2; Cancer; Oncogenes; Chronic liver disease
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10123796
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