PhD defence Y. (Yongxin) Liang

Below is a brief summary of the dissertation: 

Mild hyperthermia enhances the effectiveness of radiotherapy and chemotherapy by disrupting DNA repair. One key effect is the heat-induced degradation of BRCA2, an essential factor in homologous recombination. However, the clinical use of hyperthermia is limited by thermotolerance and activation of the heat shock response. This thesis examines ways to improve hyperthermia-based cancer treatment by targeting heat-induced protective mechanisms and by studying the molecular consequences of heat stress.

Using cervical cancer cell lines and a pre-clinical mouse model, we show that the HSP90 inhibitor ganetespib strengthens the effects of hyperthermia. It accelerates BRCA2 degradation, reduces thermotolerance, and lowers the thermal dose required for a therapeutic response. Quantitative proteomics reveals that heat stress produces widespread changes in protein ubiquitination, affecting pathways involved in DNA repair, RNA processing, and proteostasis. We also investigate BRCA2 function in more detail. We characterize the roles of individual BRCA2 domains and study how the cancer-associated W31R variant alters DNA repair capacity and RAD51 recruitment under stress conditions.

Together, these studies provide new insight into how hyperthermia interferes with genome maintenance and protein homeostasis. They also show that inhibiting HSP90 can substantially enhance the therapeutic effect of hyperthermia. This work supports the development of optimized thermal–drug combinations and improved treatment timing for future clinical applications.