LIG1 Loss Offers New Drug Combination Strategy for Aggressive Breast Cancer

Triple-negative breast cancer is among the most difficult forms of the disease to treat. It lacks the hormone receptors that make other breast cancers vulnerable to standard therapies, and when it carries mutations in the TP53 gene—a tumor suppressor—the challenge deepens. Researchers at Baylor College of Medicine, working with collaborators in London and Brazil, have discovered something counterintuitive: a genetic loss that makes these tumors resistant to chemotherapy also creates a specific weakness that can be exploited with the right drug combination.

The vulnerability centers on a gene called LIG1, which codes for DNA Ligase I, a protein involved in repairing damaged DNA. When one copy of this gene is lost in triple-negative breast cancers that also carry TP53 mutations, the cancer cells become resistant to platinum-based chemotherapy—drugs that have long been a standard treatment. This discovery, made through deep molecular profiling of tumor tissue, initially seemed like bad news for patients. But the research team, led by Dr. Meenakshi Anurag, approached it differently: if LIG1 loss creates resistance, what does that resistance depend on? What other DNA repair pathways might the cancer cells be leaning on?

The team, including graduate student Anh M. Tran-Huynh, began by testing PARP inhibitors—FDA-approved drugs that block enzymes involved in DNA repair. These showed some activity in cells with LIG1 loss, but the effect was modest. The real breakthrough came when they partnered with researchers at the Institute of Cancer Research in London to screen PARP inhibitors against a library of 120 other DNA damage response inhibitors. One combination stood out: olaparib, a PARP inhibitor, paired with ceralasertib, an ATR inhibitor. In both cell lines and animal models, this two-drug approach was significantly more effective than either drug used alone.

The mechanism appears to work like this: when LIG1 is lost, cancer cells compensate by activating alternative DNA repair pathways. By blocking both PARP and ATR—two key players in those pathways—the researchers essentially cut off the cancer cells' escape routes. The cells accumulate DNA damage they cannot repair, and the tumors shrink. The findings were published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

What makes this discovery particularly valuable for patients is the possibility of using LIG1 status as a biomarker. Before treatment begins, doctors could test a patient's tumor to determine whether LIG1 levels are low. If they are, that patient becomes a candidate for the olaparib-ceralasertib combination. This kind of precision—matching the right drug to the right genetic signature—has transformed cancer treatment in other contexts, and this work suggests it could do the same for triple-negative breast cancer. Dr. Anurag emphasized that the approach represents a shift in thinking: what began as identifying a marker of resistance became a roadmap for overcoming it.

The researchers acknowledge that the field has struggled to build on early successes with PARP inhibitors in BRCA-mutant tumors. Dr. Matthew Ellis, a co-author visiting from Brazil, noted that mechanistic understanding—knowing precisely why a drug works—is essential. LIG1 loss, he suggested, looks promising as a predictive biomarker for this particular combination therapy. The next step is clinical trials, where LIG1 status could help identify which patients are most likely to benefit. For now, the work offers hope for a population of patients with few good options: a concrete strategy, grounded in molecular biology, that transforms a genetic liability into a therapeutic opportunity.