向纤维细胞生长因子通路在割抵抗性前列腺癌分子亚型中
Mark P Labrecque1, Lisha G Brown1, Ilsa M Coleman2
1Department of Urology, University of Washington School of Medicine, Seattle, Washington, USA.
The Prostate
|October 5, 2023
概括
纤维细胞生长因子受体 (FGFR) 抑制剂在治疗多种割抵抗性前列腺癌 (CRPC) 现型方面表现有前途,包括AR阳性,AR低和AR零瘤. 虽然没有发现一种通用生物标志物,但FGFR信号是晚期前列腺癌的可行目标.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 雄激素受体 (AR) 途径的抑制是前列腺癌的标准,但在抵抗割的前列腺癌 (CRPC) 中出现了抵抗.
- 抗CRPC机制包括AR放大,AR拼接变体和AR零表型,如双阴性 (DNPC) 和小细胞/神经内分泌 (SCNPC) 前列腺癌.
- 纤维细胞生长因子受体 (FGFR) 信号绕过了DNPC中的AR依赖性,但其在其他CRPC表型中的作用尚不清楚.
研究的目的:
- 研究FGFR通路在不同CRPC表型中的作用和治疗潜力.
- 评估单独使用FGFR抑制剂 (FGFRi) 以及与AR阳性CRPC (ARPC),DNPC和SCNPC模型中与恩扎胺 (ENZA) 结合使用的FGFR抑制剂的疗效.
主要方法:
- 对转移样本,患者衍生异种移植 (PDX) 模型和CRPC细胞系进行RNA-Seq分析,以评估FGFR信号传递.
- 在体外和体外使用细胞系和PDX瘤细胞治疗ENZA和FGFR抑制剂 (erdafitinib,CH5183284) 的药物敏感性测定.
- 使用ARPC,DNPC和SCNPC的PDX模型治疗FGFR抑制剂的体内疗效研究.
主要成果:
- 在AR低的PC,DNPC和SCNPC瘤中观察到显著的FGF通路激活.
- 在ARPC,DNPC和SCNPC模型中,FGFR抑制剂显示出增长抑制,反应不同.
- 在体内,ENZA和CH5183284的联合治疗显著抑制了ARPC瘤的生长;erdafitinib单一治疗的疗效与ENZA相当.
结论:
- FGFR抑制剂抑制了各种CRPC表型的瘤生长,突出显示了FGFR途径作为标.
- 没有单一的生物标志物确定了对FGFR抑制剂有反应的瘤,这可能是由于不同的FGFR表达和CRPC表型.
- FGFR通路是一个临床可操作的瘤增长促进治疗不耐药的转移性CRPC的目标.
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