文献类型： 外文期刊

作者： Song, Xinhua ¹ ; Xu, Hongwei ¹ ; Wang, Pan ¹ ; Wang, Jingxiao ⁶ ; Affo, Silvia ⁷ ; Wang, Haichuan ¹ ; Xu, Meng ⁸ ; Liang, ¹ ;

作者机构： 1.Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

2.Univ Calif San Francisco, Liver Ctr, San Francisco, CA 94143 USA

3.Sichuan Univ, West China Hosp, Dept Liver Surg, Liver Transplantat Div, Chengdu, Peoples R China

4.Sichuan Univ, West China Hosp, Lab Liver Surg, Chengdu, Sichuan, Peoples R China

5.Beijing Acad Agr & Forestry Sci, Beijing Vegetable Res Ctr, Collaborat Innovat Ctr Agr Prod Proc & Nutr Ef Hl, Beijing, Peoples R China

6.Beijing Univ Chinese Med, Beijing, Peoples R China

7.Columbia Univ, Dept Med, New York, NY USA

8.Xi An Jiao Tong Univ, Affiliated Hosp 2, Dept Gen Surg, Xian, Peoples R China

9.Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Hepat Surg Ctr,Dept Surg, Wuhan, Peoples R China

10.Loyola Univ Chicago, Stritch Sch Med, Dept Surg & Canc Biol, Maywood, IL USA

11.Univ Calif San Francisco, Dept Surg, San Francisco, CA USA

12.Univ Regensburg, Inst Pathol, Franz Joseph Strauss Allee 11, D-93053 Regensburg, Germany

13.Univ Sassari, Dept Med Surg & Expt Sci, Sassari, Italy

14.Univ Greifswald, Inst Pathol, Greifswald, Germany

15.Legend Biotech USA Inc, R&D Ctr, Piscataway, NJ USA

关键词： intrahepatic cholangiocarcinoma; FAK; YAP; targeted therapy; cancer

期刊名称：JOURNAL OF HEPATOLOGY （ 影响因子：25.083； 五年影响因子：20.888 ）

ISSN： 0168-8278

年卷期： 2021 年 75 卷 4 期

页码：

收录情况： SCI

摘要： 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. (c) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.