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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 anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3β was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

In this study, copper-coated (Cu-coated) boron carbide (B4C) particles were successfully prepared by electroless Cu plating onto B4C particle surfaces. These Cu-coated B4C particles were combined with Cu-coated graphite particles and Cu powder, which were then used to prepare a new type of Cu-matrix self-lubricating composite by powder metallurgy. Uncoated B4C particles were used to prepare corresponding composites and all composites characterized by phase composition, microstructure, density, porosity, hardness, compressive yield strength, and friction wear. The results showed that Cu-coated B4C particles improved wettability between the particles and matrix and possessed increased interface-bonding strength with the matrix. With the same B4C content, Cu-matrix/graphite composites reinforced by Cu-coated B4C had lower porosity and wear resistance, as well as higher hardness and compressive strength, than composites reinforced by uncoated B4C. Considering the wear and friction coefficients, composites containing 0.5 wt % Cu-coated B4C exhibited better friction and wear resistance properties. [ABSTRACT FROM AUTHOR]