التفاصيل البيبلوغرافية
| العنوان: |
SLC46A3 Is Required to Transport Catabolites of Noncleavable Antibody Maytansine Conjugates from the Lysosome to the Cytoplasm. |
| المؤلفون: |
Hamblett, Kevin J.1 kjhamblett@comcast.net, Jacob, Allison P.1, Gurgel, Jesse L.1, Tometsko, Mark E.1, Rock, Brooke M.2, Patel, Sonal K.2, Milburn, Robert R.3, Siu, Sophia4, Ragan, Seamus P.5, Rock, Dan A.2, Borths, Christopher J.3, O'Neill, Jason W.4, Chang, Wesley S.6, Weidner, Margaret F.1, Bio, Matthew M.3, Quon, Kim C.1, Fanslow, William C.1 |
| المصدر: |
Cancer Research. 12/15/2015, Vol. 75 Issue 24, p5329-5340. 12p. |
| مصطلحات موضوعية: |
*ANTIBODY-drug conjugates, *CANCER treatment, *MAYTANSINE, *LYSOSOMES, *CYTOPLASM |
| مستخلص: |
Antibody-drug conjugates (ADC) target cytotoxic drugs to antigen-positive cells for treating cancer. After internalization, ADCs with noncleavable linkers are catabolized to amino acidlinker- 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 adotrastuzumab 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. [ABSTRACT FROM AUTHOR] |
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