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Genotoxic chemotherapy is the most common cancer treatment strategy. However, its untargeted generic DNA-damaging nature and associated systemic cytotoxicity greatly limit its therapeutic applications. Here, we used a haploid genetic screen in human cells to discover an absolute dependency of the clinically evaluated anticancer compound YM155 on solute carrier family member 35 F2 (SLC35F2), an uncharacterized member of the solute carrier protein family that is highly expressed in a variety of human cancers. YM155 generated DNA damage through intercalation, which was contingent on the expression of SLC35F2 and its drug-importing activity. SLC35F2 expression and YM155 sensitivity correlated across a panel of cancer cell lines, and targeted genome editing verified SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. These findings suggest a new route to targeted DNA damage by exploiting tumor and patient-specific import of YM155.

Original publication

DOI

10.1038/nchembio.1590

Type

Journal article

Journal

Nat Chem Biol

Publication Date

09/2014

Volume

10

Pages

768 - 773

Keywords

Animals, Apoptosis, Cell Division, Cell Line, Tumor, Cell Survival, Cloning, Molecular, Comet Assay, DNA Damage, Genome, Human, Haploidy, Humans, Imidazoles, Immunohistochemistry, Intercalating Agents, Membrane Transport Proteins, Mice, Mice, SCID, Naphthoquinones, RNA, Neoplasm