Endocytic evasion confers resistance to antibody-drug conjugates therapy in cancer - PubMed
4 hours ago
- #ADC resistance
- #AKR1C1 inhibition
- #Endocytic evasion
- Enfortumab vedotin (NECTIN4-ADC) is effective in urothelial carcinoma, but resistance limits long-term benefit.
- A resistant tumor cell population shows high NECTIN4 expression but defective ADC uptake, reducing intracellular payload accumulation.
- AKR1C1 binds to NECTIN4, impairing clathrin-mediated internalization and promoting extracellular vesicle-mediated ADC export via the AKR1C1-WWP2 axis.
- Pharmacologic inhibition of AKR1C1 restores ADC uptake and increases payload delivery, enhancing sensitivity in preclinical models.