The Solute Carrier SLC35F2 Enables YM155-mediated DNA Damage Toxicity

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2014 Jul 28

PMID 25064833

Citations 80

Authors

Georg E Winter

Branka Radic

Cristina Mayor-Ruiz

Vincent A Blomen

Claudia Trefzer

Richard K Kandasamy

Kilian V M Huber

Manuela Gridling

Doris Chen

Thorsten Klampfl

Robert Kralovics

Stefan Kubicek

Oscar Fernandez-Capetillo

Thijn R Brummelkamp

Giulio Superti-Furga

Affiliations

Soon will be listed here.

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.

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