抑制成纤维细胞生长因子受体 1 可抑制胰腺癌的化疗耐药性和化疗驱动的侵袭性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-02-04 DOI:10.1016/j.drup.2024.101064
Qingxiang Lin , Andrea Serratore , Jin Niu , Shichen Shen , Tista Roy Chaudhuri , Wen Wee Ma , Jun Qu , Eugene S. Kandel , Robert M. Straubinger
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引用次数: 0

摘要

目的 胰腺导管腺癌(PDAC)通常对吉西他滨等标准化疗药物具有内在耐药性。获得性吉西他滨耐药性(GemR)可能源于对最初敏感肿瘤的治疗,而化疗会增加肿瘤的侵袭性。我们研究了化疗耐药性和化疗驱动的肿瘤侵袭性的分子机制,目前对这些机制的了解尚不全面。方法采用差异蛋白质组学分析研究了不同化疗敏感性的PDAC细胞和患者衍生肿瘤异种移植物(PDX)的化疗驱动的化疗耐药性驱动因素和反应。我们还研究了FGFR1的表达在选择性泛FGFR抑制剂(FGFRi)-吉西他滨联合用药的疗效中的预后价值。FGFR1敲除或FGFRi联合治疗增强了吉西他滨的疗效并降低了GemR标记物的表达,这表明FGFR1参与了GemR的增强。FGFRi治疗可减少PDX肿瘤的进展并显著延长存活时间,即使是在单药均无疗效的高耐药性肿瘤中也是如此。根据增殖和转移标记物,吉西他滨会加剧高度吉西他滨肿瘤的侵袭性。FGFRi 与吉西他滨或吉西他滨+纳布-紫杉醇联用可逆转肿瘤的侵袭性和进展,并显著延长生存期。在多个 PDAC PDXs 中,FGFR1 的表达与肿瘤内在的吉西他滨敏感性相关。
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Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness

Aims

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.

Methods

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.

Results

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.

Conclusion

FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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