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Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness. | LitMetric

Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness.

Drug Resist Updat

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; New York State Center of Excellence in Bioinformatics & Life Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA; Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. Electronic address:

Published: March 2024

AI Article Synopsis

Article Abstract

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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Source
http://dx.doi.org/10.1016/j.drup.2024.101064DOI Listing

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