抗 FGFR 治疗伴成纤维细胞生长因子受体 (FGFR) 改变的胆管癌 (CCA) 是一种有前途的治疗选择。由于抗FGFR抑制剂和传统细胞毒性药物的抗肿瘤机制不同，因此可能具有协同作用。本研究旨在评估吉西他滨 (GEM) 和培米加替尼联合给药对 FGFR2 改变的 CCA 细胞的疗效。为了模拟 3 种 CCA 患者的治疗，即 FGF 途径激活的化疗 CCA、FGF 途径激活的化疗耐药 CCA 和无 FGF 途径激活的 CCA（作为对照），我们评估了 3 种不同的 CCA 细胞系、CCLP-1（具有 FGFR2 融合突变）、CCLP-GR（由 CCLP-1 建立的 GEM 抗性细胞）和 HuCCT1（无 FGFR 突变）。 CCLP-1和HuCCT1在GEM悬浮性方面无显着差异（IC50 = 19.3，22.6 mg/dl，p = 0.1187），并且CCLP-1和CCLP-GR对pemigatinib的药物敏感性没有差异（IC50 = 7.18） ，7.60nM，p=0.3089）。有趣的是，只有CCLP-1在体外和体内表现出与GEM加pemigatinib的联合疗法的协同作用。在与 GEM 暴露反应的比较中，只有 CCLP-1 细胞显示 FGF 通路中下游蛋白的激活增加，尤其是 FRS2 和 ERK。与此反应相关的是，细胞周期和有丝分裂随着 CCLP-1 中 GEM 暴露的增加而增加，但 HuCCT1/CCLP-GR 没有表现出此反应。我们的结果表明，GEM 联合培米加替尼联合治疗对于 FGF 通路激活的 CCA 化疗患者来说是一种有前途的治疗方法。版权所有 © 2024。由 Elsevier B.V. 出版。

Anti-FGFR treatment for cholangiocarcinoma (CCA) with fibroblast growth factor receptor (FGFR) alteration is a promising treatment option. Since the antitumor mechanisms of anti-FGFR inhibitors and conventional cytotoxic drugs differ, synergistic effects can be possible. This study aimed to evaluate the efficacy of the combined administration of gemcitabine (GEM) and pemigatinib in CCA cells with FGFR2 alterations. To simulate the treatment for patients with 3 kinds of CCA, chemonaïve CCA with activation of the FGF pathway, chemo-resistant CCA with activation of the FGF pathway, and CCA without FGF pathway activation (as controls), we evaluated 3 different CCA cell lines, CCLP-1 (with a FGFR2 fusion mutation), CCLP-GR (GEM-resistant cells established from CCLP-1), and HuCCT1 (without FGFR mutations). There was no significant difference between CCLP-1 and HuCCT1 in GEM suspensibility (IC50=19.3, 22.6 mg/dl, p=0.1187), and the drug sensitivity to pemigatinib did not differ between CCLP-1 and CCLP-GR (IC50=7.18,7.60nM, p=0.3089). Interestingly, only CCLP-1 showed a synergistic effect with combination therapy consisting of GEM plus pemigatinib in vitro and in vivo. In a comparison of the reaction to GEM exposure, only CCLP-1 cells showed an increase in the activation of downstream proteins in the FGF pathway, especially FRS2 and ERK. In association with this reaction, cell cycle and mitosis were increased with GEM exposure in CCLP-1, but HuCCT1/CCLP-GR did not show this reaction. Our results suggested that combination therapy with GEM plus pemigatinib is a promising treatment for chemonaïve patients with CCA with activation of the FGF pathway.Copyright © 2024. Published by Elsevier B.V.