Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells

Triple negative breast cancer (TNBC) represents approximately 10-15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy, and TNBC is frequently associated with a germline mutation of BRCA1. Poly (ADP-ribose) polymerase inhibitor (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Notably, increasing the RAD51 protein expression only recapitulated some, but not all, of the effects of EMI1 depletion in conferring to the cell resistance to different PARPi and the other cytotoxic drugs. These results suggest that the downstream effects of EMI1 downregulation that contribute to PARPi resistance are increasing the concentration of RAD51 protein in the cell and blocking mitotic entry. We found that combining CHK1 inhibitor with olaparib results in restoration of sensitivity even when EMI1 expression is downregulated. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.

Automated summary

Research suggests that downregulation of EMI1 leads to resistance to PARPi and other chemotherapy drugs, while increasing RAD51 protein expression partially replicates the effects of EMI1 depletion. Combining CHK1 inhibitor with olaparib can restore sensitivity even in the presence of downregulated EMI1 expression.