Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.
Mol Carcinog. 2024 Jan;63(1):173-189. doi: 10.1002/mc.23644. Epub 2023 Oct 3.
Lenvatinib is a clinically effective multikinase inhibitor approved for first-line therapy of advanced hepatocellular carcinoma (HCC). Although resistance against lenvatinib often emerges and limits its antitumor activity, the underlying molecular mechanisms involved in endogenous and acquired resistance remain elusive. In this study, we identified focal adhesion kinase (FAK) as a critical contributor to lenvatinib resistance in HCC. The elevated expression and phosphorylation of FAK were observed in both acquired and endogenous lenvatinib-resistant (LR) HCC cells. Furthermore, inhibition of FAK reversed lenvatinib resistance in vitro and in vivo. Mechanistically, FAK promoted lenvatinib resistance through regulating lysine-deficient kinase 1 (WNK1). Phosphorylation of WNK1 was significantly increased in LR-HCC cells. Further, WNK1 inhibitor WNK463 resensitized either established or endogenous LR-HCC cells to lenvatinib treatment. In addition, overexpression of WNK1 desensitized parental HCC cells to lenvatinib treatment. Conclusively, our results establish a crucial role and novel mechanism of FAK in lenvatinib resistance and suggest that targeting the FAK/WNK1 axis is a promising therapeutic strategy in HCC patients showing lenvatinib resistance.
仑伐替尼是一种临床有效的多激酶抑制剂，已被批准用于晚期肝细胞癌（HCC）的一线治疗。尽管仑伐替尼耐药经常出现并限制其抗肿瘤活性，但涉及内源性和获得性耐药的潜在分子机制仍不清楚。在这项研究中，我们确定了粘着斑激酶（FAK）是 HCC 中仑伐替尼耐药的关键贡献者。在获得性和内源性仑伐替尼耐药（LR）HCC 细胞中均观察到 FAK 的表达和磷酸化升高。此外，FAK 的抑制作用在体外和体内逆转了仑伐替尼的耐药性。在机制上，FAK 通过调节赖氨酸缺陷激酶 1（WNK1）促进了仑伐替尼的耐药性。LR-HCC 细胞中 WNK1 的磷酸化显著增加。此外，WNK1 抑制剂 WNK463 可使已建立的或内源性 LR-HCC 细胞对仑伐替尼治疗重新敏感。此外，WNK1 的过表达使亲本 HCC 细胞对仑伐替尼治疗的敏感性降低。总之，我们的研究结果确立了 FAK 在仑伐替尼耐药中的关键作用和新机制，并表明靶向 FAK/WNK1 轴是显示仑伐替尼耐药的 HCC 患者的一种有前途的治疗策略。
