Abstract
<div>AbstractPurpose:<p>Antibody–drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance.</p>Experimental Design:<p>The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, <i>in vitro</i>. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for <i>SLC46A3</i>. <i>SLC46A3</i> expression was also examined in patient-derived xenograft and <i>in vitro</i> models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR.</p>Results:<p>Loss of <i>SLC46A3</i> expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of <i>SLC46A3</i>, suggesting that expression of <i>SLC46A3</i> may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of <i>SLC46A3</i> expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs.</p>Conclusions:<p>Our findings support <i>SLC46A3</i> as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.</p></div>
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