Therapeutic Strategies for MMAE-Resistant Bladder Cancer Through DPP4 Inhibition

Monomethyl auristatin E (MMAE) is used as the cytotoxic payload for enfortumab vedotin (EV) in the treatment of locally advanced and metastatic bladder cancer (BC). However, the development of resistance to MMAE in BC is a therapeutic problem. To explore the mechanism of resistance to MMAE in BC, we established MMAE-resistant BC cells (MR-BCs). RNA sequencing analysis showed that the expression of dipeptidyl peptidase 4 (DPP4, also called CD26) increased significantly in MR-BCs compared with parental BC cells. Knock down of DPP4 expression using small interfering RNA inhibited the viability of MR-BCs. In addition, the DPP4 inhibitor sitagliptin suppressed the proliferation, migration, and invasion of BC cells, and cotreatment with MMAE effectively induced cell apoptosis, arrested cells in the G2M phase of the cell cycle, increased reactive oxygen species production by inhibiting the AKT pathway, and significantly inhibited the in vivo growth of MMAE-resistant cells. This study provides insights into the use of DPP4 inhibitors as a treatment strategy for MMAE-resistant BC. We established MMAE-resistant BC cells, MMAE-resistant T24 (MR-T24) and MMAE-resistant J82 (MR-J82). Then, we performed RNA sequencing analysis to compare gene expression levels between MR-T24 and T24, as well as MR-J82 and J82.