Transcriptional properties of LIG1-heterozygous-knockout (hetKO) vs. LIG1-WT cells in MCF-12A TP53-null and TP53-WT cells

Proteogenomic analyses has identified an association between LIG1 (DNA Ligase I) loss and chemotherapy resistance in a subset of triple negative breast cancer (TNBC) enriched for TP53 mutation. Here, we demonstrated 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 inhibitiors (PARPi) as a potential treatment for LIG1-depleted tumors, however the increase in sensitivity was modest and lower than levels 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 addition of ATR inhibitior (ATRi). Olaparib and ceralasertib demonstrated synergistic cytotoxicity in LIG1-loss cell line models; the combination significantly reduced tumor volume in LIG1-low PDX model compared to either monotherapy, and showed greater ex vivo cytotoxicity in LIG1-low PDX organoids versus LIG1-high control. Hence, this study highlights LIG1-status as a stratification factor into ongoing and future clinical trials of DDR-targeted combinations in TNBCs.