LIG1 Loss Reveals Targetable Weakness Against Chemotherapy-Resistant Triple-Negative Breast Cancer

In triple-negative breast cancer (TNBC) that carries TP53 mutations, loss of one copy of the DNA ligase I gene (LIG1) is known to blunt chemotherapy responses. Now, researchers at Baylor College of Medicine and collaborators have turned that resistance into a therapeutic weakness, mapping how platinum drugs fail—and how to force cancer cells to buckle anyway.

Using deep proteogenomic profiling, the team previously found that LIG1 loss robustly correlates with resistance, particularly to platinum-based regimens. The new study digs into the DNA-repair circuitry behind that effect, focusing on how TP53-mutant cells reorganize damage responses when LIG1 is missing.

Early experiments tested whether PARP inhibition alone could reverse the phenotype. In LIG1-loss models, PARP inhibitors such as olaparib showed only modest anti-tumor activity, suggesting that blocking a single repair node is insufficient when repair pathways are rewired downstream of LIG1 deficiency.

The researchers then broadened the hunt by pairing PARP inhibitors with agents that interfere with other DNA damage response pathways. They collaborated with investigators at the Institute of Cancer Research in London to screen PARP inhibitors alongside a larger panel of 120 DNA damage response inhibitors, seeking a combination capable of overcoming the LIG1-loss rewiring.

The most striking result was the synergy between olaparib and ceralasertib, an ATR inhibitor. In TP53-mutant/LIG1-loss cell lines, the dual blockade outperformed either drug alone, and the advantage carried into animal models where tumor growth was reduced.

Mechanistically, the work points to ATR/PARP pathway dependence as a consequence of LIG1 loss under TP53-mutant stress. In other words, the same genetic event that enables chemotherapy resistance also creates a bottleneck in how cells tolerate replication stress and DNA lesions.

Beyond therapy, the study elevates LIG1 status as a practical patient stratification marker. If LIG1 levels are low in a tumor prior to treatment, patients may be more likely to benefit from PARP–ATR combination strategies—turning genomic profiling into a real-time decision tool.

“This Achilles’ heel” framing positions LIG1-loss TNBC as a precision oncology opportunity rather than an unmanageable subtype. With ongoing and future clinical trials, validating LIG1 as a predictive biomarker could refine who gets these therapies and why, accelerating progress for a group with limited options.