Focal Adhesion Kinase (FAK) promotes cholangiocarcinoma development and progression via YAP activation.
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase upregulated in many tumor types and a promising target for cancer therapy. Here, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression.Expression levels and activation status of FAK were determined in human iCCA samples. The functional contribution of FAK to Akt/YAP murine iCCA initiation and progression was investigated using conditional Fak KO mice and constitutive Cre or inducible Cre mice, respectively. The oncogenic potential of FAK was further examined via overexpression of FAK in mice. In vitro cell line studies and in vivo drug treatment were applied to address the therapeutic potential of targeting FAK for iCCA treatment.FAK was ubiquitously upregulated and activated in iCCA lesions. Ablation of FAK strongly delayed Akt/YAP driven mouse iCCA initiation. FAK overexpression synergized with activated AKT to promote iCCA development and accelerated Akt/Jag1-driven cholangiocarcinogenesis. Mechanistically, FAK was required for YAP(Y357) phosphorylation, supporting the role of FAK as a central YAP regulator in iCCA. Significantly, ablation of FAK after Akt/YAP-dependent iCCA formation strongly suppressed tumor progression in mice. Furthermore, a remarkable iCCA growth reduction was achieved when a FAK inhibitor and Palbociclib, a CDK4/6 inhibitor, were administered simultaneously in human iCCA cell lines and Akt/YAP mice.FAK activation contributes to the initiation and progression of iCCA by inducing the YAP protooncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment.We found that Focal Adhesion Kinase (FAK) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma (iCCA) samples. FAK promotes iCCA development, whereas deletion of FAK strongly suppresses iCCA initiation and progression. Mechanistically, we discovered that FAK regulates the YAP pathway. Combined FAK and CDK4/6 inhibitor treatment is highly detrimental for the growth of in vitro and in vivo iCCA models. This combination therapy might represent a valuable and novel treatment against human iCCA.
Authors: Xinhua Song, Hongwei Xu, Pan Wang, Jingxiao Wang, Silvia Affo, Haichuan Wang, Meng Xu, Binyong Liang, Li Che, Wei Qiu, Robert F Schwabe, Tammy T Chang, Marion Vogl, Giovanni M Pes, Silvia Ribback, Matthias Evert, Xin Chen, Diego F Calvisi