Enhanced enfortumab vedotin sensitivity in a cisplatin-resistant bladder cancer model
Taisuke Tobe, Jun Teishima, Takuto Hara, Yusuke Shiraishi, Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, Yukari Bando, Kotaro Suzuki, Tomoaki Terakawa, Akihisa Yao, Koji Chiba, Hideaki MiyakeObjective
Enfortumab vedotin (EV) and cisplatin (CDDP) are central treatments for advanced urothelial carcinoma, yet the influence of prior CDDP exposure on subsequent EV efficacy remains unclear. In this report, we characterized EV-related drug responses in a CDDP-resistant bladder cancer subline.
Methods
A CDDP-resistant subline (HT1376-CR) was generated from parental bladder cancer cell (HT1376/P) through continuous exposure to CDDP. Sensitivities to CDDP, EV, and the EV payload monomethyl auristatin E (MMAE) were compared between HT1376-CR and HT1376/P. Nectin-4 expression, EV binding, and drug-resistance-related gene expression were evaluated. The effect of ABCB1 silencing on drug response was also examined. In vivo EV responses were explored using xenograft models.
Results
HT1376-CR cells showed increased sensitivity to EV in vitro and in vivo. HT1376-CR cells were more sensitive to MMAE and showed greater G2/M accumulation after MMAE exposure. In contrast, cell-surface nectin-4 expression and EV binding were reduced. ABCB1 was markedly upregulated in HT1376-CR, and ABCB1 silencing increased sensitivity to CDDP, MMAE, and EV within the resistant subline.
Conclusion
The CDDP-resistant HT1376 subline showed enhanced sensitivity to EV, and ABCB1 suppression further increased EV sensitivity within this resistant subline.