Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
FASEB J. 2023 Apr;37(4):e22840. doi: 10.1096/fj.202201247R.
Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.
厄达替尼是一种新型成纤维细胞生长因子受体（FGFR）抑制剂，对 FGFR3 改变的实体瘤患者具有很大的治疗潜力，尤其是在膀胱癌中。然而，FGFR 抑制剂耐药的机制仍知之甚少。在这项研究中，我们发现厄达替尼可以通过诱导不完全自噬和增加细胞内活性氧水平来杀死细胞。我们建立了厄达替尼耐药细胞系 RT-112-RS。对厄达替尼耐药的 RT-112-RS 细胞和亲本 RT-112 细胞进行全转录组 RNA 测序（RNA-Seq）和 Cytospace 分析，结果显示 P4HA2 是厄达替尼耐药的关键因素。功能获得和功能丧失研究为 P4HA2 在 RT-112 细胞中赋予这种耐药性提供了证据。此外，P4HA2 可以稳定 HIF-1α 蛋白，从而激活下游靶基因，降低膀胱癌中的活性氧水平。反过来，HIF-1α 可以直接结合 P4HA2 启动子，表明膀胱癌中 P4HA2 和 HIF-1α 之间存在正反馈环。这些结果表明 P4HA2 在介导获得性厄达替尼耐药中起重要作用，并为膀胱癌治疗提供了一个潜在的靶点。
