LIG1 Loss Reveals Drug Vulnerability in Triple‑Negative Breast Cancer

Researchers at Baylor College of Medicine, together with collaborators, have uncovered a new therapeutic angle for triple‑negative breast cancers (TNBC) that harbor TP53 mutations and lose one copy of the DNA ligase I (LIG1) gene. The loss of LIG1 confers resistance to standard chemotherapy, particularly platinum‑based agents, by disrupting DNA repair pathways. In the study published in *Molecular Cancer Therapeutics*, the team mapped the molecular mechanisms that drive this resistance and demonstrated that combining existing drugs can neutralize the vulnerability created by LIG1 loss, leading to significant tumor shrinkage in animal models.

The investigators identified that TNBC cells with TP53 mutations and LIG1 haploinsufficiency rely on alternative DNA repair pathways to survive platinum treatment. By targeting these compensatory mechanisms with drug combinations—such as inhibitors of poly(ADP‑ribose) polymerase (PARP) and checkpoint kinases—they were able to restore chemosensitivity and reduce tumor growth in preclinical experiments. The study also proposes that LIG1 status could serve as a biomarker for patient stratification in ongoing and future clinical trials, enabling more precise selection of patients who are likely to benefit from these targeted combination therapies.

These findings highlight a promising strategy to overcome chemotherapy resistance in a subset of aggressive breast cancers. By exploiting the specific genetic alterations that underlie treatment failure, the research opens a pathway to more effective, personalized therapeutic regimens for patients with TP53‑mutant, LIG1‑deficient TNBC.