Abstract 5581: The DACH1 gene, frequently co-deleted with BRCA2 in prostate cancer, governs PARP inhibitor resistance

Abstract

Abstract Background: Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities (1,2). The DACH1 gene, in the 13q21.31-q21.33 region, encodes a winged helix/Forkhead DNA-binding protein that governs cell-fate determination that is deleted in ~ 18% of human PCa, where it is associated with poor prognosis (3). Prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN). Methods: Analysis of DACH1 gene deletion and expression was conducted from public data bases and human prostate cancer samples. Cells derived from Dach1 gene deletion mice and human prostate cancer cell lines with DACH1 overexpression were analyzed for PARP inhibitor responses and mechanisms of PARPi resistance. Transgenic prostate Oncomice were generated in which the Dach1 gene was deleted in the prostate. Results: Herein, DACH1 was shown to be co-deleted with BRCA2 in each of 8 separate cohorts (N=2,186 patients), in ~3-12% of patients. Dach1 gene deletion or knockdown conferred PARP inhibitor resistance (talazoparib > niraparib > olaparib > rucaparib > veliparib). DACH1 enhanced PARP sensitivity through several mechanisms affecting replication stress, PARP1 binding, inhibiting G9a (reducing H3K9me2), inhibiting CHK1p and CDK1p and inducing expression of snoRNA, specifically the snoRNA known to bind PARP. PARP1 has a BRCT (BRCA1 C-terminus 1) homology domain governing PARP1 dimerization and binding to intact DNA in a complex within a nucleosome. DACH1 binding to PARP1 requires the BRCT domain. Conclusions: There is a correlation between DACH1a-/- and PARPi resistance, correlating with PARPi trapping ability. As reduced Dach1a expression may define a subclass of PCa that warrants specific therapies, testing for DACH1a may be warranted.