Numerous mechanisms may be responsible for T-DM1 resistance: (1) reduced HER2 expression, reduced T-DM1 binding, dysregulated PI3K signaling, signaling through alternative RTKs, and the tumor immune set point; (2) intratumor heterogeneity in HER2 expression and accessibility; (3) altered internalization of HER2–T-DM1 complexes; and (4) impaired lysosomal release of lysine-MCC-DM1(Hunter et al., 2020) (Table 1; Figure 1). The gene discussed is ERBB2; the disease is neoplasm.