成纤维细胞生长因子受体1
癌症研究
细胞生长
基因敲除
吉西他滨
胰腺癌
成纤维细胞生长因子受体
小发夹RNA
细胞迁移
生物
生长因子
细胞
细胞培养
癌症
成纤维细胞生长因子
受体
生物化学
遗传学
作者
Qingxiang Lin,Andrea Serratore,Jonathan Perri,Tista Roy Chaudhuri,Jun Qu,Wen Wee,Eugene Kandel,Robert M. Straubinger
摘要
Abstract Background and Purpose Elevated fibroblast growth factor receptor (FGFR) activity correlates with pancreatic adenocarcinoma (PDAC) progression and poor prognosis. However, its potential as a therapeutic target remains largely unexplored. Experimental Approach The mechanisms of action and therapeutic effects of selective pan‐FGFR inhibitors (pan‐FGFRi) were explored using in vitro and in vivo PDAC models ranging from gemcitabine‐sensitive to highly gemcitabine‐resistant (GemR). Gain‐/loss‐of‐function investigations were employed to define the role of individual FGFRs in cell proliferation, migration, and treatment response and resistance. Results The pan‐FGFRi NVP‐BGJ398 significantly inhibited cell proliferation, migration, and invasion, and downregulated key cell survival‐ and invasiveness markers in multiple PDAC cell lines. Gemcitabine is a standard‐of‐care for PDAC, but development of resistance to gemcitabine (GemR) compromises its efficacy. Acquired GemR was modelled experimentally by developing highly GemR cells using escalating gemcitabine exposure in vitro and in vivo. FGFRi treatment inhibited GemR cell proliferation, migration, GemR marker expression, and tumour progression. FGFR2 or FGFR3 loss‐of‐function by shRNA knockdown failed to decrease cell growth, whereas FGFR1 knockdown was lethal. FGFR1 overexpression promoted cell migration more than proliferation, and reduced FGFRi‐mediated inhibition of proliferation and migration. Single‐agent FGFRi suppressed the viability and growth of multiple patient‐derived xenografts inversely with respect to FGFR1 expression, underscoring the influence of FGFR1‐dependent tumour responses to FGFRi. Importantly, secondary data analysis showed that PDAC tumours expressed FGFR1 at lower levels than in normal pancreas tissue. Conclusions and Implications Single‐agent FGFR inhibitors mediate selective, molecularly‐targeted suppression of PDAC proliferation, and their effects are greatest in PDAC tumours expressing low‐to‐moderate levels of FGFR1.
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