High glucose associated YTHDC1 lactaylation reduces the sensitivity of bladder cancer to enfortumab vedotin therapy

Hyperglycemia has been reported to be a risk factor for bladder cancer (BC). Enfortumab vedotin (EV), the first antibody-drug conjugates targeting NECTIN4, has shown promising clinical efficacy in patients with advanced BC. However, the impact of high glucose status on EV sensitivity remains unclear. In this study, we discover that EV treatment in BC patients with diabetes is less effective than those of patients with normal blood glucose. The subsequent cell and mice studies indicate that high glucose decreases the sensitivity of BC cells to EV. We previously reported that high glucose results in decreased protein levels of YTHDC1, promoting the tumorigenesis of BC cells. Our study identifies a high glucose associated lactate-AARS1-YTHDC1-JUND-NECTIN4 axis that affects EV sensitivity in BC. Targeting this axis with JUND activator or ß-alanine may offer therapeutic strategies to enhance the sensitivity of BC cells to EV. Overall design: Comparative gene expression profiling analysis of RNA-seq data for the HT1376 cells. WFI vs. Enfortumab vedotin.