The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity
Genetic requirement for drug action is important to study as it may reveal mechanism of drug resistance, particularly in cancer, as well as generate ideas for better, safer and more personalized drugs. The laboratory of CeMM Director Giulio Superti-Furga used a genetic screen with human haploid cells, based on the work of Thijn Brummelkamp and his team (NKI and CeMM Adjunct PI), to identify the genes affecting the action of a poorly understood cancer drug under clinical evaluation. Surprisingly, only one gene turned out to lead to resistance, the uncharacterized member of the solute carrier SLC35F2. Further studies showed that whether this cancer drug works or not is entirely dependent on the presence of this transporter. In fact, there is a strong correlation between the levels of expression of the transporter and sensitivity to the drug. If the door is open, the drug will go through and kill the cell.
The findings have been published advanced online in the journal Nature Chemical Biology: The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. 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. Nature Chemical Biology. doi:10.1038/nchembio.1590.
SLC are the neglected gates that regulate access to biological systems to chemistry, or of organisms to the environment. CeMM is dedicated to mount a large interdisciplinary effort involving several laboratories to try to crack the “code” of the transport and regulation specificity. This will take several years but will allow to have better targeted drugs, that are safer because they know where they go, and to understand the relationship between drugs and nutrition.