Loss of one copy of the DNA ligase I (LIG1) gene in triple-negative breast cancers (TNBC) with TP53 mutations confers resistance to chemotherapy, but researchers at Baylor College of Medicine and collaborating institutions have identified a vulnerability in these cells and used it to their advantage. The team identified underlying molecular mechanisms of platinum resistance that they neutralized with combinations of available drugs to reduce tumor growth in animal models. This work also highlights LIG1 status as a patient stratification factor for ongoing and future clinical trials. The study appeared in Molecular Cancer Therapeutics.
"In a previous study, using deep proteogenomic profiling of TNBC tumors, we found that LIG1 loss is robustly associated with chemotherapy resistance, especially to platinum agents, in TNBCs with TP53 mutations," said co-corresponding author Dr. Meenakshi Anurag, assistant professor of medicine and a member of the Lester and Sue Smith Breast Center at Baylor. "In pursuit of identifying a better treatment for these patients, we tried to better understand the molecular impact of LIG1 loss and how to use it to our advantage."
"We focused on DNA repair mechanisms activated by LIG1 loss in TP53-mutant models to identify a therapeutic Achilles' heel in chemotherapy-resistant TNBC," said first author Anh M. Tran-Huynh, a graduate student in the Anurag lab. "Based on scientific evidence, we initially examined PARP inhibition by testing FDA-approved drugs that block PARP enzymes involved in repairing damaged DNA. PARP inhibitors showed modest activity in our LIG1-loss models."
