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 , a journal of the American Association for Cancer Research.
"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 part of the Lester and Sue Smith Breast Center at Baylor. "In pursuit of identifying a better treatment for these patients, we tried to deeply 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 on 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."
The team subsequently collaborated with Dr. Christopher Lord and Dr. Andrew Tutt at the Institute of Cancer Research in London to screen PARP inhibitors in combination with 120 DNA damage response inhibitors. "We were excited to observe that combining olaparib, a PARP inhibitor, and ceralasertib, an ATR inhibitor, was significantly more effective than each drug alone in TP53-mutant/LIG1-loss cell lines as well as animal models," Tran-Huynh said.
"For me, the most exciting part of this study was the multidisciplinary approach that led us to identify a new therapy for these difficult to treat TNBC tumors," Anurag said. "We started by identifying LIG1 loss as a marker of chemotherapy resistance, initially a negative finding for TNBC patients. The question became whether we could leverage this discovery to identify a clinical-grade treatment strategy for these high-risk TNBCs. We have now identified a drug combination with the potential to improve outcomes for these patients."
Importantly, the authors hope that LIG1 can be used as a biomarker to identify TNBC patients as candidates for this combination therapy in future clinical trials. "Determining LIG1 status in a patient's breast cancer tumor before therapy can inform treatment decisions," Anurag said. "If a tumor's LIG1 levels are low, then this patient is probably a good candidate for the combination therapy."
"After a huge win with PARP inhibition, the DNA repair inhibitor, the field has struggled despite the development of a large repertoire of drugs against alternative targets," said Dr. Matthew Ellis, co-corresponding author and visiting professor at the State University of Campinas, Sao Paulo, Brazil. "The effectiveness of PARP inhibitors in BRCA1- and BRCA2-deficient tumors taught us that a mechanistic approach is critical. LIG1 loss therefore looks promising as a predictive biomarker for ATR/PARP inhibitor combinations."
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