Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely. Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations. Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity. FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.

中文翻译：

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成纤维细胞生长因子受体 1 抑制可抑制胰腺癌化疗耐药性和化疗驱动的侵袭性


胰腺导管腺癌 (PDAC) 通常对吉西他滨等标准化疗具有内在耐药性。获得性吉西他滨耐药性 (GemR) 可能是由于治疗最初敏感的肿瘤而产生的，化疗会增加肿瘤的侵袭性。我们研究了化疗耐药和化疗驱动的肿瘤侵袭性的分子机制，但目前尚不完全了解。采用差异蛋白质组分析来研究化疗驱动的化疗耐药驱动因素以及具有不同化疗敏感性的 PDAC 细胞和患者来源的肿瘤异种移植物 (PDX) 的反应。我们还研究了 FGFR1 表达对选择性泛 FGFR 抑制剂 (FGFRi)-吉西他滨组合疗效的预后价值。对高 GemR 细胞系的定量蛋白质组分析表明，成纤维细胞生长因子受体 1 (FGFR1) 是表达最高的受体酪氨酸激酶。 FGFR1 敲低或 FGFRi 联合治疗增强了吉西他滨的功效并降低了 GemR 标记物的表达，表明 FGFR1 增强了 GemR。 FGFRi 治疗显着减少了 PDX 肿瘤进展并延长了生存期，即使是在单药均​​未显示疗效的高度耐药肿瘤中也是如此。根据增殖和转移标志物，吉西他滨加剧了高 GemR 肿瘤的侵袭性。 FGFRi 与吉西他滨或吉西他滨+白蛋白结合型紫杉醇组合可逆转肿瘤侵袭性和进展，并显着延长生存期。在多个 PDAC PDX 中，FGFR1 表达与肿瘤固有的吉西他滨敏感性相关。 FGFR1 驱动化疗耐药性和肿瘤侵袭性，FGFRi 可以逆转这一现象。