Table 2.

Mechanisms of resistance and of the overcoming of resistance.

Mechanism of Resistance		Overcoming Resistance
Antigen-related resistance	■Reduced HER2/NECTIN 4 levels ■Tumor heterogeneity ■Truncated forms of antigen ectodomain ■Parallel genomic alteration ■Heregulin	■Bystander effect ■Biparatropic ADC
Payload-related resistance	■DAR ■Payload conjugation	■Payload diversification: replacement of payload (auristatin vs. anthracycline based, topoisomerase I vs. belotecan derivative) ■Lysine vs. cysteine conjugate
Altered internalization	■Microenvironment and enzymatic role
Impaired lysosomal function	■Lysosomal pH	■Replacement of hydrophobic with hydrophilic linkers
Overexpression of drug-efflux pumps	■ATP-binding cassette (ABC) transporters	■Aberrant expression of transporters ■Transporter inhibition
Activation of signaling pathways	■PI3K/AKT signaling activation ■Wnt/β-catenin pathway	■Combination therapies