Cell cycle deregulation is involved in pathogenesis of many cancers, and often associated with protein kinase aberrations, including the polo-like kinase 1 (PLK1). Wehereby used retinoblastoma, an intraocular malignancy that lacks targeted therapy, as a disease model and set out to reveal targetability of PLK1 with a small molecularinhibitor ON-01910.Na. First, transcriptomic analysis on patient retinoblastoma tissues suggested that cell cycle progression was deregulated and confirmed that PLK1pathway was upregulated. Next, antitumor activity of ON-01910.Na was investigated inboth cellular and animal levels. Cytotoxicity induced by ON-01910.Na was tumor-specific and dose-dependent in retinoblastoma cells, whilst non-tumor cells wereminimally affected. In three-dimensional culture, ON-01910.Na demonstrated efficient drug-penetrability with multilayer cell death. Post-treatment transcriptomic findingsrevealed that cell cycle arrest and MAPK cascade activation were induced following PLK1 inhibition, and eventually result in apoptotic cell death. In Balb/c nude mice, a safe threshold of 0.8 nmol intravitreal dosage of ON-01910.Na was established for intraocular safety, which was demonstrated by structural integrity and functional preservation. Furthermore, intraocular and subcutaneous xenograft were significantlyreduced with ON-01910.Na treatments. For the first time, we demonstrated targetability of PLK1 in retinoblastoma by efficiently causing cell cycle arrest and apoptosis. Ourstudy is supportive that local treatment of ON-01910.Na may be a novel, effectivemodality benefiting patients with PLK1-aberrant tumors.
A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype
