PARP1-selective inhibitor DSB1559 demonstrates superior efficacy and antitumor immunity in triple-negative breast cancer

Abstract

Abstract Background Poly (ADP-ribose) polymerase inhibitors (PARPis) have improved outcomes of BRCA-associated breast cancer; however, treatment-related toxicity remains a major clinical challenge. Currently approved PARPis broadly inhibit multiple members of the PARP protein family. However, preclinical studies suggest that inhibition of PARP1 alone is sufficient to drive antitumor efficacy. In contrast, inhibition of PARP2 has been implicated in hematological toxicities seen in patients receiving PARPi therapy. Therefore, selectively inhibiting PARP1 may reduce toxicity for patients. Here, we characterize and test the PARP1-selective inhibitor DSB1559 in preclinical models of Brca1-associated triple-negative breast cancer (TNBC). Methods Pharmacokinetic/pharmacodynamic assays were performed to examine DSB1559 potency, selectivity, and in vivo behavior. Immunocompetent FVB/n mice bearing Brca1-deficient TNBC (CMV-Cre;Brca1fl/fl;Trp53fl/fl) tumors were treated with olaparib or DSB1559 and followed for survival. Flow cytometry and bulk RNA-sequencing were performed to measure the effects on the tumor microenvironment (TME). Results DSB1559 had superior selectivity for PARP1 and increased overall survival compared with olaparib. Analysis of the TME revealed a significant increase in cytotoxic T-cells, activated dendritic cells, and genes associated with antitumor immunity in mice treated with DSB1559. Conclusions Taken together, DSB1559 is a highly selective PARP1 inhibitor that demonstrates superior efficacy and antitumor immune response compared with olaparib. A structurally related, clinical lead compound (DSB2455) is now being tested in a phase Ia/Ib clinical trial (NCT06458712).