The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity

• Published in: Nature chemical biology Vol. 10; no. 9; pp. 768 - 773
• Main Authors: Winter, Georg E, Radic, Branka, Mayor-Ruiz, Cristina, Blomen, Vincent A, Trefzer, Claudia, Kandasamy, Richard K, Huber, Kilian V M, Gridling, Manuela, Chen, Doris, Klampfl, Thorsten, Kralovics, Robert, Kubicek, Stefan, Fernandez-Capetillo, Oscar, Brummelkamp, Thijn R, Superti-Furga, Giulio
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2014; Nature Publishing Group
• Subjects: 45; 45/23; 45/91; 631/337/1427; 631/67; 631/80/82; 631/92/93; Animals; Apoptosis - drug effects; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cancer therapies; Cell Biology; Cell Division - drug effects; Cell Division - physiology; Cell Line, Tumor; Cell Survival; Chemistry; Chemistry/Food Science; Chemotherapy; Cloning, Molecular; Comet Assay; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Drug resistance; Genes; Genome, Human - drug effects; Genome, Human - genetics; Genomes; Haploidy; Humans; Imidazoles - metabolism; Imidazoles - pharmacology; Immunohistochemistry; Intercalating Agents - pharmacology; Medical research; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Mice, SCID; Mutagenesis; Mutation; Naphthoquinones - metabolism; Naphthoquinones - pharmacology; Proteins; RNA, Neoplasm - chemistry; RNA, Neoplasm - genetics; Toxicity; Netherlands
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.1590

A haploid screen in human cells identified the solute carrier protein family member, SLC35F2, as a determinant of the sensitivity of cells to the DNA damaging agent, YM155, by promoting YM155 import into cells. 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.