Mechanisms of resistance to FGFR inhibitors in the treatment of advanced cholangiocarcinoma with FGFR mutations: A literature review

Abstract

Advanced cholangiocarcinoma harbors various genetic alterations, one of the most common being fibroblast growth factor receptor (FGFR) fusions. Although FGFR inhibitors have a good response rate, their median progression-free survival is about 6 - 9 months in most trials. The present manuscript is a non-systematic review that explores the mechanisms of resistance and the possible strategies to overcome this rapid resistance. From the findings, resistance to FGFR inhibition can be classified into either primary or secondary resistance. Primary resistance is less common, explained mostly by the presence of co-mutations. In contrast, secondary resistance mechanisms are similar to other tyrosine kinase inhibitors: On-target mutations alter the binding site of the FGFR protein (gatekeeper resistance); off-target mechanisms are multifactorial and involve the activation of related intracellular pathways and the loss of differentiation, leading to a mesenchymal phenotype. Various strategies are in development in order to maintain the efficacy of targeted therapy for patients by overcoming FGFR inhibition resistance, including the coinhibition of the related pathway, the use of pan-FGFR inhibitors, and the development of covalent or dual FGFR inhibitors.

Keywords

Cholangiocarcinoma / FGFR inhibitor / Resistance / Mechanism

References

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