The development of new, efficient medicinal treatments for cholangiocarcinoma (CCA) was an unmet need. YAP, an effector in the Hippo pathway that causes cancer in CCA, had previously been challenging to target therapeutically. YAP is activated by tyrosine phosphorylation by the Src-family kinase LCK, as researchers recently described. It resulted from the idea that LCK is a workable therapeutic target in CCA through control of YAP activity.

Pharmacodynamic profiles of NTRC 0652-0, a new tyrosine kinase inhibitor with significant selectivity for LCK, were created in vitro and in CCA cells. Eight CCA patient-derived organoids (PDO) were examined and evaluated for NTRC 0652-0 sensitivity. For the in vivo evaluation of pharmacokinetics, toxicity, and effectiveness, two patient-derived xenografts (PDX) models with FGFR2 rearrangements were used.

In vitro and in CCA cells, NTRC 0652-0 showed selectivity for LCK inhibition. Inhibiting LCK with NTRC 0652-0 caused YAP’s co-transcriptional activity, nuclear localization, and tyrosine phosphorylation to diminish, which in turn caused apoptotic cell death in CCA cell lines. A portion of the examined patient-derived organoids showed NTRC 0652-0 sensitivity. A genetic subgroup of CCA with FGFR2 fusions was shown to be potentially vulnerable and clinically relevant. Daily oral administration of NTRC 0652-0 to PDX models of FGFR2 fusion-positive CCA led to steady plasma and tumor drug levels, tolerable tolerability, decreased YAP tyrosine phosphorylation, and markedly reduced tumor growth.

A new LCK inhibitor, NTRC 0652-0, reduced YAP signaling and showed preclinical effectiveness in patient-derived organoid and xenograft models as well as CCA cell lines.