Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies
Purpose: Hyperthermia (40–44 °C) effectively sensitises tumours to radiotherapy by locally altering tumour biology. One of the effects of heat at the cellular level is inhibition of DNA repair by homologous recombination via degradation of the BRCA2-protein. This suggests that hyperthermia can expand the group of patients that benefit from PARP-inhibitors, a drug exploiting homologous recombination deficiency. Here, we explore whether the molecular mechanisms that cause heat-mediated degradation of BRCA2 are conserved in cell lines from various origins and, most importantly, whether, BRCA2 protein levels can be attenuated by heat in freshly biopted human tumours. Experimental design: Cells from four established cell lines and from freshly biopsied material of cervical (15), head- and neck (9) or bladder tumours (27) were heated to 42 °C for 60 min ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumour: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting. Results: We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumours treated ex vivo. For tumours treated with hyperthermia in vivo, technical issues and intra-tumour heterogeneity prevented obtaining interpretable results. Conclusions: This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumour material directly derived from patients. Although BRCA2-degradation may not be a practical biomarker for heat deposition in situ, it does suggest that application of hyperthermia could be an effective method to expand the patient group that could benefit from PARP-inhibitors.
|Keywords||BRCA2, DNA repair, homologous recombination, Hyperthermia, PARP-inhibitors|
|Persistent URL||dx.doi.org/10.1080/02656736.2017.1355487, hdl.handle.net/1765/101070|
|Journal||International Journal of Hyperthermia|
|Grant||This work was funded by the European Commission 7th Framework Programme; grant id fp7/259893 - The DNA damage response and breast cancer (DDRESPONSE)|
van den Tempel, N, Odijk, H, van Holthe, N, Naipal, K.A.T, Raams, A, Eppink, B, … Kanaar, R. (2017). Heat-induced BRCA2 degradation in human tumours provides rationale for hyperthermia-PARP-inhibitor combination therapies. International Journal of Hyperthermia, 1–8. doi:10.1080/02656736.2017.1355487