SLC46A3 Is Required to Transport Catabolites of Noncleavable Antibody Maytansine Conjugates from the Lysosome to the Cytoplasm
| Autor: | Allison P. Jacob, Christopher J. Borths, Matthew M. Bio, Sophia Siu, Mark E. Tometsko, Kevin J. Hamblett, Jason W. O'Neill, Jesse L. Gurgel, Seamus Ragan, Margaret F. Weidner, William C. Fanslow, Brooke M. Rock, Wesley Chang, Kim Quon, Robert R. Milburn, Dan A. Rock, Sonal K. Patel |
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| Rok vydání: | 2015 |
| Předmět: |
Cytoplasm
Cancer Research Immunoconjugates media_common.quotation_subject Small hairpin RNA Drug Delivery Systems Cell Line Tumor Lysosome medicine Humans Maytansine Internalization media_common biology Membrane transport protein Membrane Transport Proteins Transporter Antineoplastic Agents Phytogenic body regions Monomethyl auristatin F medicine.anatomical_structure Oncology Biochemistry Cell culture biology.protein Lysosomes medicine.drug |
| Zdroj: | Cancer Research. 75:5329-5340 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-15-1610 |
| Popis: | Antibody–drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acid-linker-warheads within the lysosome, which then enter the cytoplasm by an unknown mechanism. We hypothesized that a lysosomal transporter was responsible for delivering noncleavable ADC catabolites into the cytoplasm. To identify candidate transporters, we performed a phenotypic shRNA screen with an anti-CD70 maytansine-based ADC. This screen revealed the lysosomal membrane protein SLC46A3, the genetic attenuation of which inhibited the potency of multiple noncleavable antibody–maytansine ADCs, including ado-trastuzumab emtansine. In contrast, the potencies of noncleavable ADCs carrying the structurally distinct monomethyl auristatin F were unaffected by SLC46A3 attenuation. Structure–activity experiments suggested that maytansine is a substrate for SLC46A3. Notably, SLC46A3 silencing led to relative increases in catabolite concentrations in the lysosome. Taken together, our results establish SLC46A3 as a direct transporter of maytansine-based catabolites from the lysosome to the cytoplasm, prompting further investigation of SLC46A3 as a predictive response marker in breast cancer specimens. Cancer Res; 75(24); 5329–40. ©2015 AACR. |
| Databáze: | OpenAIRE |
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