LIG1 Loss in TP53-mutant Triple Negative Breast Cancer Rewires DNA Repair and Confers Sensitivity to PARP-ATR...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Proteogenomic analysis reveals LIG1 loss is linked to chemotherapy resistance in a subset of triple-negative breast cancer (TNBC) with TP53 mutations.
• TP53 mutations and LIG1 loss are associated with increased DNA damage response (DDR) activity, including homologous recombination, potentially reducing platinum sensitivity.

Purpose of the Study:

• To investigate the therapeutic potential of targeting DNA repair pathways in LIG1-deficient TNBC.
• To identify effective drug combinations for LIG1-loss TNBC models.

Main Methods:

• Utilized unbiased genetic and monotherapy drug screens to identify potential treatments for LIG1-depleted tumors.
• Conducted a screen of PARP inhibition combined with 120 clinically relevant DDR inhibitors.
• Evaluated synergistic cytotoxicity of olaparib and ceralasertib in LIG1-loss cell lines and patient-derived xenograft (PDX) models.

Main Results:

• PARP inhibitors (PARPi) showed modest sensitivity increase in LIG1-depleted TNBC, less than in homologous recombination-deficient models.
• PARPi sensitivity was significantly enhanced by ATR inhibitors (ATRi) in LIG1-loss cells.
• The combination of olaparib and ceralasertib demonstrated synergistic cytotoxicity, reduced tumor volume in a LIG1-low PDX model, and enhanced ex vivo cytotoxicity.

Conclusions:

• LIG1 loss is a potential stratification biomarker for DDR-targeted therapies in TNBC.
• The combination of ATR inhibitors and PARP inhibitors offers a promising therapeutic strategy for LIG1-deficient TNBC.
• LIG1 status can guide patient selection for ongoing and future clinical trials involving DDR-targeted combinations in TNBC.