The following is a summary of the “LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma,” published in the January 2023 issue of Hepatology by Conboy et al.
Novel and effective medicinal therapy for cholangiocarcinoma (CCA) is needed. Yes-associated protein (YAP), a member of the Hippo pathway, is carcinogenic in CCA but has been difficult to target therapeutically. Activation of YAP via tyrosine phosphorylation is a recently described function of the Src family tyrosine kinase (LCK) proto-oncogene. Results suggested that LCK, via controlling YAP activity, could be a useful therapeutic target in CCA. Pharmacodynamic profiling in vitro and CCA cells was done on the new tyrosine kinase inhibitor NTRC 0652-0, showing some LCK selectivity.
They identified eight organoids generated from CCA patients and examined them for sensitivity to NTRC 0652-0. The in vivo pharmacokinetics, toxicity, and efficacy were evaluated using 2 patient-derived xenograft models, including fibroblast growth factor receptor 2 (FGFR2)-rearrangements. Selectivity for LCK inhibition was proven in vitro and CCA cells using NTRC 0652-0. Reducing tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP via inhibition of LCK with NTRC 0652-0 caused apoptotic cell death in CCA cell lines. In addition, NTRC 0652-0 was active in some of the examined patient-derived organoids.
It has been found that CCAs with FGFR2 fusions represent a genetic subset of CCAs that may be particularly vulnerable and clinically important. Consistent plasma and tumor drug levels, tolerable tolerability, decreased YAP tyrosine phosphorylation, and markedly reduced tumor growth were seen after daily oral therapy with NTRC 0652-0 in patient-derived xenograft models of FGFR2 fusion-positive CCA. Preclinical efficacy was shown in CCA cell lines, as well as patient-derived organoid and xenograft models, where the new LCK inhibitor NTRC 0652-0 suppressed YAP signaling.
Source: sciencedirect.com/science/article/pii/S016882782203121X