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Hamblett, Kevin J; Jacob, Allison P; Gurgel, Jesse L; Tometsko, Mark E; Rock, Brooke M; Patel, Sonal K; Milburn, Robert R; Siu, Sophia; Ragan, Seamus P; Rock, Dan A; Borths, Christopher J; O'Neill, Jason W; Chang, Wesley S; Weidner, Margaret F; Bio, Matthew M; Quon, Kim C; Fanslow, William C
Cancer research (Chicago, Ill.), 12/2015, Letnik: 75, Številka: 24Journal Article
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.
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in: SICRIS
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