Triple-negative breast cancer remains among the most treatment-resistant malignancies precisely because it lacks the molecular handles — hormone receptors, HER2 amplification — that allow targeted therapy in other breast cancer subtypes. A new mechanistic study suggests that loss of a specific DNA repair enzyme, DNA Ligase I (LIG1), may define a clinically actionable subset of TNBC patients who could benefit from a drug combination not yet widely considered for this context.
In TP53-mutant TNBC — already one of the most genomically chaotic cancer subtypes — LIG1 loss was found to upregulate homologous recombination (HR) activity and other DNA damage response (DDR) pathways, a paradox that simultaneously drives platinum chemotherapy resistance and creates a new therapeutic vulnerability. A systematic screen of 120 clinically relevant DDR inhibitors layered onto PARP inhibition revealed that ATR inhibition (ATRi) dramatically amplifies the cytotoxic effect of PARP inhibitors in LIG1-depleted models. The PARP inhibitor olaparib combined with the ATR inhibitor ceralasertib demonstrated synergistic cell killing across LIG1-loss cell lines, significantly reduced tumor volume in a patient-derived xenograft (PDX) model, and showed superior ex vivo cytotoxicity in a LIG1-low patient-derived organoid (PDXO) model compared to either agent alone.
This work is scientifically notable for several reasons. PARP inhibitors have historically been reserved for BRCA1/2-mutant or HR-deficient tumors; LIG1-loss tumors appear to occupy a distinct mechanistic niche — HR-proficient yet still PARP/ATR-sensitive — that challenges the prevailing patient-selection framework. The authors propose LIG1 status as a biomarker for stratifying patients in ongoing and future clinical trials. Limitations include the absence of clinical outcome data and reliance on preclinical models, though the inclusion of PDX and organoid systems adds translational weight. If these findings hold in early-phase trials, LIG1 testing could become a meaningful addition to TNBC molecular profiling.