Heat-induced BRCA2 degradation in human tumors provides rationale for hyperthermia-PARP-inhibitor combination therapies

Hyperthermia (40-44°C) effectively sensitizes tumors to radiotherapy by locally altering tumor 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 tumors.

Cells from four established cell lines and from freshly biopsied material of cervical (15), head- and neck (9) or bladder tumors (27) were heated to 42°C for 60 minutes ex vivo. In vivo hyperthermia was studied by taking two biopsies of the same breast or cervical tumor: one before and one after treatment. BRCA2 protein levels were measured by immunoblotting.

We found decreased BRCA2-levels after hyperthermia in all established cell lines and in 91% of all tumors treated ex vivo. For tumors treated with hyperthermia in vivo, technical issues and intra-tumor heterogeneity prevented obtaining interpretable results.

This study demonstrates that heat-mediated degradation of BRCA2 occurs in tumor 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.

International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. 2017 Jul 13 [Epub ahead of print]

Nathalie van den Tempel, Hanny Odijk, Netteke van Holthe, Kishan Naipal, Anja Raams, Berina Eppink, Dik van Gent, Jose Hardillo, Gerda Verduijn, Jan Drooger, Gerard van Rhoon, Dineke Smedts, Helena van Doorn, Joost Boormans, Agnes Jager, Martine Franckena, Roland Kanaar

a Department of Molecular Genetics , Cancer Genomics Center Netherlands, Erasmus University Medical Center , Rotterdam , The Netherlands., b Department of Radiation Oncology , Erasmus MC Cancer Institute , Rotterdam , The Netherlands., c Department of Otolaryngology and Head and Neck Surgery , Erasmus University Medical Center , Rotterdam , The Netherlands., d Department of Medical Oncology , Ikazia Hospital , Rotterdam , The Netherlands., e Department of Gynaecological Oncology , Erasmus University Medical Centre , Rotterdam , The Netherlands., f Department of Urology , Erasmus MC Cancer Institute , Rotterdam , The Netherlands., g Department of Medical Oncology , Erasmus MC Cancer Institute , Rotterdam , The Netherlands.