胆管癌(CCA)是一种难以治疗的癌症,有限的治疗选择和手术是唯一的治愈性治疗。标准化疗包括以吉西他滨为基础的联合顺铂治疗,奥沙利铂,卡培他滨,或5-FU,大多数患者预后不佳。受体酪氨酸激酶(RTK)在包含潜在治疗机会的CCA中异常表达。因此,在KKU-M213细胞中筛选出112种RTK抑制剂,和ceritinib,一种被批准的ALK融合基因驱动癌症的靶向疗法,是最有力的候选人.Ceritinib在CCA中的细胞毒性使用MTT和克隆试验进行评估,随着免疫荧光,westernblot,和qRT-PCR技术分析基因表达和信号变化。此外,使用ZIP协同作用评分确定了色瑞替尼和顺铂之间的药物相互作用关系.此外,采用球体和异种移植模型来研究ceritinib的体内疗效。我们的研究表明,色瑞替尼在临床相关血浆浓度下有效杀死CCA细胞,与ALK表达或突变状态无关。Ceritinib调节多个信号通路,导致PI3K/Akt/mTOR通路的抑制,并激活细胞凋亡和自噬。此外,色瑞替尼和顺铂协同降低CCA细胞活力。我们的数据显示ceritinib是CCA的有效治疗方法,这可能在没有ALK突变的其他癌症类型中进行探索。
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and
ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib\'s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between
ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of
ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally,
ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show
ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.