Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition
Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5°C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized ondemand induction of HR deficiency, an approach that we term induced synthetic lethality.
|Keywords||Anti-cancer treatment, Double-strand break, RAD51|
|Persistent URL||dx.doi.org/10.1073/pnas.1101053108, hdl.handle.net/1765/33400|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id fp7/259893 - The DNA damage response and breast cancer (DDRESPONSE)|
Krawczyk, P.M, Eppink, B, Essers, J, Stap, J, Rodermond, H, Odijk, H, … Aten, J.A. (2011). Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proceedings of the National Academy of Sciences of the United States of America, 108(24), 9851–9856. doi:10.1073/pnas.1101053108