Investigating the rationale for cabozantinib use in patients with cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly aggressive malignancy of the biliary tree classified into intra- (iCCA) and extra-hepatic (eCCA) subtypes based on its anatomical localization. The poor overall survival (OS) of this cancer, due to late diagnosis and therapeutic resistance onset, makes the development of novel therapeutic options urgently needed. Cabozantinib, a multitarget tyrosine kinase inhibitor (TKI), has been approved for the treatment of different types of cancer due to its high efficacy. However, this small molecule has not been thoroughly explored for CCA treatment and the only available clinical study presents serious limitations. In the present study, we provide proof of concept for the use of cabozantinib in CCA by assessing its ability to inhibit Mesenchymal Epithelial Transition Factor (MET) and Vascular Endothelial Growth Factor Receptor (VEGFR2), two tyrosine kinase receptors (TKR) that modulate survival, proliferation, and migration pathways driving tumour progression. Our analyses reveal that approximately 75% of patients expressed at least one of the receptors, with VEGFR2 significantly higher in eCCA patients. Notably, we show that cabozantinib significantly reduces proliferation and migration in a panel of CCA cell lines, with the only exception of SSP25 cell line which does not effectively respond to the treatment. Moreover, we show that cabozantinib impairs endothelial cell activation within the same concentration range inhibiting cancer cell proliferation, thereby suppressing angiogenesis and enhancing drug antitumor effect. Finally, we provide evidence that cabozantinib effectively inhibits MET- and VEGFR2-driven signalling, specifically Protein Kinase B (AKT) and Mitogen Activated Protein Kinase (MAPK) pathways. Overall, our preliminary findings suggest the feasibility of cabozantinib for CCA treatment by directly linking its effects to the downregulation of MET- and VEGFR2-mediated signalling pathways in CCA cells.