title: The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.
abstract: 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.
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Georg E
authors: GE
authors: Winter
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Branka
authors: B
authors: Radic
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Cristina
authors: C
authors: Mayor-Ruiz
authors: Division of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors: Vincent A
authors: VA
authors: Blomen
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Claudia
authors: C
authors: Trefzer
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Richard K
authors: RK
authors: Kandasamy
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Kilian V M
authors: KVM
authors: Huber
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Manuela
authors: M
authors: Gridling
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Doris
authors: D
authors: Chen
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Thorsten
authors: T
authors: Klampfl
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Robert
authors: R
authors: Kralovics
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Stefan
authors: S
authors: Kubicek
authors: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Oscar
authors: O
authors: Fernandez-Capetillo
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.|Division of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors: Thijn R
authors: TR
authors: Brummelkamp
authors: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14 1090 Vienna, Austria.
authors: Giulio
authors: G
authors: Superti-Furga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D003001:Cloning, Molecular; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D015894:Genome, Human / Q000187:drug effects / Q000235:genetics; D006238:Haploidy; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D007150:Immunohistochemistry; D007364:Intercalating Agents / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics
chemical_list: D007093:Imidazoles; D007364:Intercalating Agents; D026901:Membrane Transport Proteins; D009285:Naphthoquinones; D012334:RNA, Neoplasm; C569094:SLC35F2 protein, human; C523798:sepantronium