Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics that enable targeted delivery of cytotoxic drugs to cancer cells. Although clinical efficacy has been demonstrated for ADC therapies, resistance to these conjugates may occur. Recently, SLC46A3, a lysosomal membrane protein, was revealed to regulate the efficacy of trastuzumab emtansine (T-DM1), a noncleavable ADC that has been widely used for treating breast cancer. However, the role of SLC46A3 in mediating T-DM1 cytotoxicity remains unclear. In this study, we discovered the function of SLC46A3 as a novel proton-coupled steroid conjugate and bile acid transporter. SLC46A3 preferentially recognized lipophilic steroid conjugates and bile acids as endogenous substrates. In addition, we found that SLC46A3 directly transports Lys-SMCC-DM1, a major catabolite of T-DM1, and potent SLC46A3 inhibitors attenuate the cytotoxic effects of T-DM1, suggesting a role in the escape of Lys-SMCC-DM1 from the lysosome into the cytoplasm. Our findings reveal the molecular mechanism by which T-DM1 kills cancer cells and may contribute to the rational development of ADCs that target SLC46A3.

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Co-administration of methotrexate (MTX) and proton pump inhibitors (PPIs) is reported to increase serum MTX concentrations in patients receiving high-dose MTX therapy. However, the range of MTX high dosage is wide. We attempted to clarify the effects of PPIs co-administration on the elimination of MTX at the fixed dose of 1 g/m 2 in a retrospective cohort study of 46 patients with hematological malignancies who underwent a total of 91 cycles of chemotherapy. Data on gender, age, concomitant drugs, and laboratory test results were analyzed. The median and first to third quartile of MTX concentrations with and without PPI co-administration at 24, 48, and 72 h postdosing were 17.

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