Investigation of the molecular mechanisms of the synergy between erdafitinib and quisinostat. Investigation of the molecular mechanisms of the synergy between erdafitinib and quisinostat

We first verified that erdafitinib is synergistic with quisinostat in vitro and confirmed that the combinational treatment can significantly enhance the inhibition of tumor growth and prolong the survival in vivo for bladder cancers with FGFR3 fusions. Next, in order to understand the underlying molecular mechanisms of this synergy, we performed RNA-seq analysis. We revealed that quisinostat can concomitantly inhibit FGFR signaling with erdafitinib by suppressing the translation of FGFR3 fusions. In addition, quisinostat can also sensitize bladder cancer cells to erdafitinib by downregulating HDGF, which is a second mechanism of the synergy independent of FGFR signaling. Overall design: We have three bladder cancer cell lines with FGFR3 fusions: RT4, RT112, and SW780. We treated all three cells with quisinostat or DMSO control. And then we extracted mRNA and performed RNA-seq analysis.

我们首先验证了厄达替尼（erdafitinib）与喹司他特（quisinostat）在体外具备协同作用，并证实联合给药可显著抑制携带FGFR3融合基因的膀胱癌的体内肿瘤生长，同时延长模型动物的生存期。为阐明该协同作用的潜在分子机制，我们开展了RNA测序（RNA-seq）分析。结果显示，喹司他特可通过抑制FGFR3融合基因的翻译过程，与厄达替尼协同阻断FGFR信号通路。此外，喹司他特还可通过下调肝癌衍生生长因子（HDGF）使膀胱癌细胞对厄达替尼产生增敏效应，这是不依赖FGFR信号通路的第二种协同作用机制。实验总体设计：我们选用3株携带FGFR3融合基因的膀胱癌细胞系：RT4、RT112及SW780。分别使用喹司他特或二甲基亚砜（DMSO）对照处理这三株细胞，随后提取总mRNA并进行RNA测序分析。