Background: Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models.
Materials and Methods: HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model.
Results: Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response.
Conclusion: Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.



中文翻译：

---

Pan-HER 抑制剂 Varlitinib 对胆管癌细胞系的体外和体内抗肿瘤作用。

背景：胆管癌（CCA）是一种进展缓慢但具有高度侵袭性的恶性肿瘤。靶向 HER 蛋白家族代表了一种潜在的 CCA 治疗策略。pan-HER 抑制剂 varlitinib 正在开发用于治疗乳腺癌、胃癌和胆道癌，其中包括 CCA。本研究旨在使用体外和体内模型评估 varlitinib 对 CCA 的抗肿瘤作用。
材料和方法：在 CCA 细胞系（KKU-214、KKU-213、KKU-156 和 KKU-100）和胆管细胞（MMNK-1）中测定 HER 家族表达谱和 varlitinib 的细胞毒活性。在 KKU-214 和 KKU-100 细胞系中检查了抗增殖和细胞凋亡诱导。研究了 varlitinib 与 PI3K 抑制剂 BKM-120 的组合在 KKU-100 细胞系中的功效。此外，在来自 CCA 异种移植模型的肿瘤组织中评估了 varlitinib 对 CCA 和关键代谢物的抗肿瘤活性。
结果：在 KKU-214 和 KKU-100 细胞中观察到 EGFR 和 HER2 的表达升高，varlitinib 可以在微摩尔范围内抑制 CCA 细胞的生长。Varlitinib 通过抑制 KKU-214 细胞系中的 Akt 和 Erk1/2 活性来抑制细胞增殖并增强细胞死亡。虽然 KKU-100 细胞对 varlitinib 反应不佳，但 varlitinib 与 BKM-120 的组合提高了抗肿瘤活性。Varlitinib 可在口服给药 15 天后显着抑制 CCA 异种移植模型中的肿瘤生长而无明显毒性，并且天冬氨酸可能是与 varlitinib 反应相关的关键代谢物。
结论：我们的研究表明，varlitinib 通过抑制 EGFR/HER2 是一种很有前景的 CCA 治疗药物。varlitinib 对 CCA 的抗肿瘤作用也显示出与 PI3K 抑制相结合的协同作用。天冬氨酸代谢物水平与伐利替尼反应相关。建议将伐利替尼与靶向药物或细胞毒药物联合使用。