Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
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.
J Hepatol. 2021 Oct;75(4):888-899. doi: 10.1016/j.jhep.2021.05.018. Epub 2021 May 28.
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.
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.
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 proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment.
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.
黏着斑激酶（FAK）是一种非受体酪氨酸激酶，在许多肿瘤类型中上调，是癌症治疗的一个有前途的靶点。在此，我们阐明了 FAK 在肝内胆管癌（iCCA）发展和进展中的功能作用。
测定了人 iCCA 样本中 FAK 的表达水平和激活状态。分别使用条件性 Fak 敲除小鼠和组成型 Cre 或诱导型 Cre 小鼠，研究了 FAK 对 Akt/YAP 小鼠 iCCA 起始和进展的功能贡献。通过在小鼠中过表达 FAK 进一步研究了 FAK 的致癌潜力。应用体外细胞系研究和体内药物治疗来解决针对 FAK 治疗 iCCA 的治疗潜力。
FAK 在 iCCA 病变中广泛上调和激活。FAK 的缺失强烈延迟了 Akt/YAP 驱动的小鼠 iCCA 起始。FAK 的过表达与激活的 AKT 协同作用，促进 iCCA 的发展，并加速 Akt/Jag1 驱动的胆管癌发生。在机制上，FAK 是 YAP(Y357)磷酸化所必需的，支持 FAK 作为 iCCA 中中央 YAP 调节剂的作用。重要的是，在 Akt/YAP 依赖性 iCCA 形成后，FAK 的缺失强烈抑制了小鼠肿瘤的进展。此外，在人类 iCCA 细胞系和 Akt/YAP 小鼠中同时给予 FAK 抑制剂和 palbociclib（一种 CDK4/6 抑制剂），可显著抑制 iCCA 的生长。
FAK 的激活通过诱导 YAP 原癌基因促进 iCCA 的起始和进展。单独靶向 FAK 或与抗 CDK4/6 抑制剂联合使用，可能是 iCCA 治疗的有效策略。
我们发现蛋白 FAK（黏着斑激酶）在人及鼠肝内胆管癌样本中上调和激活。FAK 促进肝内胆管癌的发展，而 FAK 的缺失强烈抑制其起始和进展。在体外和体内模型中，FAK 和 CDK4/6 抑制剂联合治疗具有强烈的抗癌作用。这种联合治疗可能是针对人类肝内胆管癌的一种有价值的新治疗方法。
