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

Proteogenomic analyses have identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutations. Here, we demonstrate that co-occurrence of TP53 mutations and LIG1 loss is associated with upregulated DDR activity, including homologous recombination, likely contributing to reduced platinum sensitivity. Unbiased genetic and monotherapy drug screens identified PARP inhibitors (PARPi) as a potential treatment for LIG1-depleted tumors; however, the increase in sensitivity was modest and lower than that observed in TNBC models with homologous recombination deficiency. Subsequently, a screen of PARP inhibition in combination with each of 120 clinically relevant DDR inhibitors revealed that PARPi sensitivity in LIG1-loss cells was significantly enhanced by the addition of an ATR inhibitor (ATRi). Olaparib and ceralasertib demonstrated synergistic cytotoxicity in LIG1-loss cell line models; the combination significantly reduced tumor volume in a LIG1-low PDX model compared to either monotherapy, and showed greater ex vivo cytotoxicity in a LIG1-low PDXO model versus a LIG1-high control. Hence, this study highlights LIG1 status as a stratification factor for ongoing and future clinical trials of DDR-targeted combinations in TNBCs.