Xinhua Song1, Hongwei Xu2, Pan Wang3, Jingxiao Wang4, Silvia Affo5, Haichuan Wang2, Meng Xu6, Binyong Liang7, Li Che8, Wei Qiu9, Robert F Schwabe5, Tammy T Chang10, Marion Vogl11, Giovanni M Pes12, Silvia Ribback13, Matthias Evert11, Xin Chen14, Diego F Calvisi15. 1. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. Electronic address: songxinhua0726@yeah.net. 2. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China. 3. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA; Collaborative Innovation Center for Agricultural Product Processing and Nutrition & Health, Beijing Vegetable Research Center, Beijing Academy of Agriculture and Forestry Science, Beijing, China. 4. Beijing University of Chinese Medicine, Beijing, China. 5. Department of Medicine, Columbia University, New York, NY, USA. 6. Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China. 7. Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 8. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. 9. Department of Surgery and Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA. 10. Department of Surgery and Liver Center, University of California, San Francisco, CA, USA. 11. Institute of Pathology, University of Regensburg, Regensburg, Germany. 12. Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy. 13. Institute of Pathology, University of Greifswald, Greifswald, Germany. 14. Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA. Electronic address: xin.chen@ucsf.edu. 15. Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de.
Abstract
BACKGROUND & AIMS: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is upregulated in many tumor types and is a promising target for cancer therapy. Herein, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression. METHODS: 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 knockout 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. RESULTS: 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. CONCLUSIONS: FAK activation contributes to the initiation and progression of iCCA by inducing the YAP proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment. LAY SUMMARY: We found that the protein FAK (focal adhesion kinase) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma samples. FAK promotes intrahepatic cholangiocarcinoma development, whereas deletion of FAK strongly suppresses its initiation and progression. Combined FAK and CDK4/6 inhibitor treatment had a strong anti-cancer effect in in vitro and in vivo models. This combination therapy might represent a valuable and novel treatment against human intrahepatic cholangiocarcinoma.
BACKGROUND & AIMS: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is upregulated in many tumor types and is a promising target for cancer therapy. Herein, we elucidated the functional role of FAK in intrahepatic cholangiocarcinoma (iCCA) development and progression. METHODS: 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 knockout 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. RESULTS: 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. CONCLUSIONS: FAK activation contributes to the initiation and progression of iCCA by inducing the YAP proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment. LAY SUMMARY: We found that the protein FAK (focal adhesion kinase) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma samples. FAK promotes intrahepatic cholangiocarcinoma development, whereas deletion of FAK strongly suppresses its initiation and progression. Combined FAK and CDK4/6 inhibitor treatment had a strong anti-cancer effect in in vitro and in vivo models. This combination therapy might represent a valuable and novel treatment against human intrahepatic cholangiocarcinoma.
Authors: Shanshan Zhang; Xinhua Song; Dan Cao; Zhong Xu; Biao Fan; Li Che; Junjie Hu; Bin Chen; Mingjie Dong; Maria G Pilo; Antonio Cigliano; Katja Evert; Silvia Ribback; Frank Dombrowski; Rosa M Pascale; Antonio Cossu; Gianpaolo Vidili; Alberto Porcu; Maria M Simile; Giovanni M Pes; Gianluigi Giannelli; John Gordan; Lixin Wei; Matthias Evert; Wenming Cong; Diego F Calvisi; Xin Chen Journal: J Hepatol Date: 2017-07-19 Impact factor: 25.083
Authors: Sumera Rizvi; Shahid A Khan; Christopher L Hallemeier; Robin K Kelley; Gregory J Gores Journal: Nat Rev Clin Oncol Date: 2017-10-10 Impact factor: 66.675
Authors: L Che; B Fan; M G Pilo; Z Xu; Y Liu; A Cigliano; A Cossu; G Palmieri; R M Pascale; A Porcu; G Vidili; M Serra; F Dombrowski; S Ribback; D F Calvisi; X Chen Journal: Oncogenesis Date: 2016-12-05 Impact factor: 7.485
Authors: Yuhua Wei; Yufeng Wang; Nanbin Liu; Ran Qi; Yan Xu; Kun Li; Yu Feng; Baomin Shi Journal: Front Pharmacol Date: 2022-01-18 Impact factor: 5.810