Therapeutic potential of PCNA and HDAC inhibitor combinations in cutaneous T-cell lymphoma and other cancers

AOH1996, a small molecule inhibitor designed to target protein binding of proliferating cell nuclear antigen (PCNA) in cancer, was previously shown to inhibit cell growth across the NCI-60 human tumor cell line screen with minimal toxicity to nonmalignant cells. Guided by post-translational modification signature enrichment analysis of phosphorylated proteins after AOH1996 treatment, we tested its combination with histone deacetylase inhibitors (HDACi) belinostat and vorinostat. Treatment with AOH1996 and HDACi showed synergistic growth inhibition in neuroblastoma, breast, colon, and cutaneous T-cell lymphoma (CTCL) cell lines. A CRISPR interference screen and selective HDACi studies suggested that the synergy with AOH1996 involved HDAC3 and HDAC6. Furthermore, AOH1996 combined with vorinostat or romidepsin, both FDA-approved for treatment of CTCL, showed synergistic growth inhibition in four cell lines derived from CTCL. Mechanistic studies revealed enhanced DNA damage response, cell cycle arrest, and apoptosis in CTCL cells treated with AOH1996 and HDACi. These findings support the therapeutic potential of combining AOH1996 with HDACi for the treatment of cancers, including CTCL.