Therapeutic Inhibition of Fibroblast Growth Factor and YAP Signaling in Cholangiocarcinoma

This project in the Mayo Clinic Hepatobiliary SPORE is examining the cellular mechanisms by which intrahepatic cholangiocarcinoma (cancer of the bile ducts) develops and progresses. Project researchers are determining if disruption of these signals results in tumor cell death and therapeutic cancer regression in preclinical models and in a proof-of-concept clinical trial.

Both the Hippo and fibroblast growth factor receptor 2 (FGFR2) signaling pathways have been implicated as oncogenic mediators in intrahepatic cholangiocarcinoma. Project researchers are unifying these observations by positing cross-talk between the Hippo and FGFR2 signaling pathways in intrahepatic cholangiocarcinoma.

The project team has generated preliminary data demonstrating that Hippo signaling via activation of the transcriptional coactivator YES-associated protein (YAP) drives expression of FGFR2, and that FGFR2 signaling mediates YAP activation. Further evaluation of the pathway has demonstrated that tyrosine phosphorylation of YAP appears to be dependent on Src family kinases. Tyrosine-phosphorylated YAP, in turn, associates with TBX5, driving oncogenic transcriptional activity.

From a preclinical therapeutic perspective, inhibition of FGFR2 signaling induces tumor cell death in patient-derived xenografts with YAP nuclear immunoreactivity but not in those negative for this marker of Hippo pathway signaling.

Hypothesis

Project researchers hypothesize that intrahepatic cholangiocarcinoma progression can be driven by FGFR2-mediated YAP tyrosine phosphorylation by Src family kinases.

Project aims

The aims of this research project on intrahepatic cholangiocarcinoma are to:

  • Test the hypothesis that YAP drives specific FGFR2 expression, which in turn promotes YAP signaling by: (a) FGFR-mediated Src family kinases activation and YAP tyrosine phosphorylation; and (b) tyrosine-phosphorylated YAP coactivated by the TBX5-mediated transcriptional expression of FGFR family members
  • Test the hypothesis that YAP nuclear localization serves as a biomarker for response to FGFR2-targeted therapy: (a) in unselected patient-derived xenografts treated with an FGFR inhibitor; and (b) in conjunction with evidence for a YAP activation signature in patient-derived xenografts
  • Test the hypothesis that inhibition of FGFR signaling is therapeutic in patients with intrahepatic cholangiocarcinoma: (a) in patients with FGFR2 fusion negative/YAP nuclear positive cholangiocarcinoma who are receiving INCB054828, a panFGFR inhibitor, in the setting of a clinical trial; and (b) by interruption of Hippo signaling pathways

The results of these studies have the potential to provide greater understanding of intrahepatic cholangiocarcinoma biology and identify new therapeutic strategies coupled with biomarkers for the treatment of this cancer.