Dual role of the unfolded protein response in the therapeutic effect of AZD1775 on TP53 mutant high grade serous ovarian cancer

we demonstrate that the WEE1 inhibitor AZD1775 triggers endoplasmic reticulum (ER) stress and activates the PERK and IRE1α branches of the unfolded protein response (UPR) in TP53 mutant HGSOC cells. Upon AZD1775 treatment, PERK facilitates apoptotic signaling in these cells via activating CHOP, whereas IRE1α-induced spliced XBP1 (XBP1s) confers survival in response to WEE1 inhibition. Our data uncover an important dual role of UPR in TP53 mutant HGSOC cells in response to AZD1775, where additional inhibition of IRE1α-XBP1s signaling may offer synergistic efficacy. OVCAR8 cells were treated with DMSO or AZD1775 and the mRNA expression levels were detected by RNA-seq.

本研究证实，WEE1抑制剂AZD1775可诱发TP53突变型高级别浆液性卵巢癌（high-grade serous ovarian carcinoma, HGSOC）细胞产生内质网（endoplasmic reticulum, ER）应激，并激活未折叠蛋白反应（unfolded protein response, UPR）的PERK与IRE1α通路分支。经AZD1775处理后，PERK可通过激活C/EBP同源蛋白（C/EBP homologous protein, CHOP）促进此类细胞的凋亡信号通路；而IRE1α诱导的剪接型X盒结合蛋白1（spliced X-box binding protein 1, XBP1s）则可在WEE1抑制过程中赋予细胞生存优势。本研究数据揭示了未折叠蛋白反应在TP53突变型HGSOC细胞响应AZD1775过程中发挥的重要双重作用，即联合抑制IRE1α-XBP1s信号通路或可产生协同治疗效应。本研究以二甲基亚砜（dimethyl sulfoxide, DMSO）与AZD1775处理OVCAR8细胞，并通过RNA测序（RNA-sequencing, RNA-seq）检测细胞的mRNA表达水平。