New Biomarker Helps Guide Combination Therapy for Treatment-Resistant Breast Cancer

Identifying biomarkers that signal resistance while pointing to actionable treatment strategies remains a clinical need. New findings demonstrate a biomarker-defined vulnerability that can be targeted with existing agents.

Baylor College of Medicine (Houston, TX, USA) researchers and collaborators identified loss of one copy of DNA ligase I (LIG1) as a marker of chemotherapy resistance in TP53-mutant TNBC and a potential basis for patient stratification. The team showed that this genomic alteration creates a dependency in DNA repair pathways that can be therapeutically targeted, positioning LIG1 status as a possible guide for treatment selection in clinical studies.

Mechanistically, investigators examined DNA repair programs activated by LIG1 loss and evaluated PARP inhibition using U.S. Food and Drug Administration (FDA)-approved drugs, which produced only modest activity in LIG1-loss models. They then partnered with the Institute of Cancer Research in London to screen PARP inhibitors alongside 120 DNA damage response inhibitors. This approach identified combined blockade of PARP and ATR as a rational strategy in the TP53-mutant/LIG1-loss setting.

In preclinical testing, combining olaparib, a PARP inhibitor, with ceralasertib, an ATR inhibitor, was significantly more effective than either agent alone in TP53-mutant/LIG1-loss cell lines and animal models. The combination reduced tumor growth in animals, indicating that LIG1 loss creates a therapeutically exploitable vulnerability in chemotherapy-resistant TNBC. The authors note that LIG1 status could serve as a patient selection biomarker in ongoing and future clinical trials.

The study, “LIG1 Loss in TP53‑mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP‑ATR Inhibitor Combinations,” was published in Molecular Cancer Therapeutics. Conducted at Baylor College of Medicine with collaborating institutions, including the Institute of Cancer Research in London, the work underscores the potential role of LIG1 testing to inform therapeutic decisions before initiating treatment.

“Determining LIG1 status in a patient’s breast cancer tumor before therapy can inform treatment decisions. If a tumor’s LIG1 levels are low, the patient is probably a good candidate for the combination therapy,” said Dr. Meenakshi Anurag, assistant professor of medicine and a member of the Lester and Sue Smith Breast Center at Baylor.

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