LIG1 Loss Exposes Therapeutic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer
核心洞察
Loss of one copy of the DNA Ligase I (LIG1 (搜索)) gene in TP53 (搜索)-mutant triple-negative breast cancers is robustly associated with platinum-based chemotherapy resistance.
Researchers identified that combining the PARP (搜索) inhibitor olaparib with the ATR inhibitor ceralasertib was significantly more effective than either drug alone in LIG1 (搜索)-loss models.
The study, published in Molecular Cancer Therapeutics, demonstrated reduced tumor growth in animal models using this combination strategy.
Loss of one copy of the DNA Ligase I (LIG1 (搜索)) gene in triple-negative breast cancers (TNBC) harboring TP53 (搜索) mutations confers resistance to platinum-based chemotherapy, but researchers at Baylor College of Medicine and collaborating institutions have turned this liability into a therapeutic opportunity. The team identified the molecular mechanisms underlying platinum resistance and neutralized them using a combination of two existing drugs, achieving significant tumor growth reduction in animal models. The findings, published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research, also position LIG1 status as a patient stratification factor for ongoing and future clinical trials.
From a Negative Finding to a Therapeutic Strategy
The study builds on prior proteogenomic profiling work from the same group. "In a previous study, using deep proteogenomic profiling of TNBC tumors we found that LIG1 (搜索) loss is robustly associated with chemotherapy resistance, especially to platinum agents, in TNBCs with TP53 (搜索) 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 deeply understand the molecular impact of LIG1 loss and how to use it to our advantage."
The research team focused on DNA repair mechanisms activated by LIG1 (搜索) loss in TP53 (搜索) mutant models. "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.
PARP (搜索) Inhibition Alone Shows Modest Activity
The team's initial approach examined PARP (搜索) inhibition using FDA-approved drugs that block PARP enzymes involved in repairing damaged DNA. However, PARP inhibitors as single agents showed only modest activity in the LIG1 (搜索)-loss models, prompting the researchers to explore combination strategies.
A Powerful Combination Emerges
In collaboration with Dr. Christopher Lord and Dr. Andrew Tutt at the Institute of Cancer Research in London, the team screened PARP (搜索) inhibitors in combination with 120 DNA damage response inhibitors. This systematic approach yielded a striking result. "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 (搜索)-mutant/LIG1 (搜索)-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 (搜索) 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."
LIG1 (搜索) as a Predictive Biomarker
The authors emphasize that LIG1 (搜索) could serve as a biomarker to identify TNBC patients who are 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 explained. "If a tumor's LIG1 levels are low, then this patient is probably a good candidate for the combination therapy."
Dr. Matthew Ellis, co-corresponding author and visiting professor at the State University of Campinas in São Paulo, Brazil, placed the findings in broader context. "After a huge win with PARP (搜索) inhibition, the DNA repair inhibitor, the field has struggled despite the development of a large repertoire of drugs against alternative targets," Ellis said. "The effectiveness of PARP inhibitors in BRCA1- and BRCA2-deficient tumors taught us that a mechanistic approach is critical. LIG1 (搜索) loss therefore looks promising as a predictive biomarker for ATR/PARP inhibitor combinations."