Thioparib Inhibits Homologous Recombination Repair, Activates the Type-I IFN Response, and Overcomes Olaparib Resistance

ABSTRACT: Poly ADP-ribose polymerase (PARP) inhibitors (PARPi) have shown great promise for treating BRCA-deficient tumors. However, over 40% of BRCA-deficient patients fail to respond to PARPi. Here we report that thioparib, a next-generation PARPi with high affinity against multiple PARPs, including PARP1, PARP2, and PARP7, displays high antitumor activities against PARPi-sensitive and -resistant cells with homologous recombination (HR) deficiency both in vitro and in vivo. Thioparib treatment elicited PARP1-dependent DNA damage and replication stress, causing S-phase arrest and apoptosis. Conversely, thioparib strongly inhibited HR-mediated DNA repair while increasing RAD51 foci formation. Notably, the on-target inhibition of PARP7 by thioparib activated STING/TBK1-dependent phosphorylation of ST

SUBMITTER: Limin Wang 

PROVIDER: S-SCDT-10_15252-EMMM_202216235 | biostudies-other |

REPOSITORIES: biostudies-other