Targeting RAD51-BRCA2 interaction in the search for novel anticancer and chemosensitizer drug candidates

Genome integrity is constantly affected by DNA damage and replication errors due to exogenous and endogenous sources. Cells have developed several strategies to counteract these threats detecting DNA damages and mediating its repair through different mechanisms depending on the specificity of the DNA lesion. Cancer cells are more sensitive to these insults compared to normal cells and most therapeutic strategy indeed rely on inducing specific lethal DNA damages. The urgent need for new therapeutic strategies in cancer treatment is due to the frequent development of resistance to therapeutic induced DNA damage. Through a multidisciplinary project, comprising a computational, a synthetic, a biology as well as a biophysical contribution, we aim at applying a synthetic lethality approach in cancer cell therapy by preventing, with small molecules, the viable hRAD51-BRCA2 interaction. The latter interaction plays a key role in the repair of double strand breaks (DSBs) within the homologous recombination (HR) pathway. The leading idea of our project is mimicking the synthetic lethality induced in BRCA2 defective oncology patients by olaparib, a poly ADP ribose polymerase (PARP) inhibitor. We aim at increasing cancer cells sensitivity to PARPi and at broadening PARPi applicability by administering, in combination with the latter inhibitors, hRAD51-BRCA2 small molecules disruptors also to individuals without BRCA2 mutations. The goal of my PhD research project is the characterization of the hRAD51-BRCA2 interaction through a biophysical approach, in order to gain kinetic and thermodynamic insights on this critical junction of the HR pathway, and through a structural approach, to elucidate the atomic details of the interaction. My research work is concurrently a critical support for the overall project, which aims at the development of a new drug and at the validation of a broaden applicability of the synthetic lethality concept.