Pol theta: Study of resistance pathways in tumors associated with Homologous Recombination Deficiency (HRD)

Resistance to chemotherapy and PARP inhibitors remains a major challenge in the treatment of ovarian cancer. The introduction of PARP inhibitors has significantly improved the prognosis of patients with ovarian cancer, including those harboring BRCA1/2 mutations as well as Homologous Recombination Deficiency-positive and HRD-negative tumors. However, important questions remain regarding the adaptive pathways that enable tumor cells to develop resistance mechanisms. This study aimed to identify genes potentially involved in alternative DNA repair pathways that may cooperate with or compensate for HRR. We primarily focused on POLQ due to its central role in Theta-Mediated End Joining (TMEJ). Additionally, emerging evidence have drawn our attention to other genes, including APEX2, ALDH1A1, FANCD2, and FEN1. Our analyses evaluated patterns of deregulation and loss of expression of these genes across 2 patient cohorts (mutated cohort and wild-type cohort). Differential expression between HRD and HR-proficient tumors was observed for each gene, suggesting distinct adaptive repair strategies. These findings provide preliminary insight into the potential prognostic and predictive relevance of the analyzed genes and support further investigation into their role in drug resistance.