Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.

ABSTRACT: Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3β and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased

SUBMITTER: Zhang N 

PROVIDER: S-EPMC7884722 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature