P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer

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.

Erdafitinib; HIF-1α; P4HA2; bladder cancer; drug resistance; fibroblast growth factor receptor 3.