Therapeutic Targeting PLK1 by ON-01910.Na Is Effective in Local Treatment of Retinoblastoma

Abstract

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.

Another Brick to Confirm the Efficacy of Rigosertib as Anticancer Agent

“…The 100 nm Rig concentration is consistent with Rig concentrations used in other studies; in fact, in all these works, Rig exhibited the same efficacy in reducing the viability of the cell lines evaluated, with effective concentrations starting approximately at 50–100 nM [ 6 , 14 , 15 , 16 , 17 , 18 ].…”

“…Moreover, Rig is capable of inducing senescence or cell death by apoptosis in several tumor cell lines, both in vitro and in vivo [ 4 , 6 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], increasing the production of ROS and altering the expression of numerous proteins involved in apoptosis (p53, BAX, MDM2) and in the formation of metastases (E-cadherins, matrix metalloproteinases 2 and 9) [ 5 ].…”

“…In the last few years, Rig has been evaluated in several clinical trials for the treatment of myelodysplastic syndromes, alone or in combination with other drugs [ 20 , 21 , 22 , 23 ]. Furthermore, various articles in literature have demonstrated the efficacy of Rig in vitro also in different types of solid tumors, such as colorectal cancer (SW48 and CaCo2 cells), neuroblastoma (LU-NB1, LU-NB2, LU-NB3 cells), retinoblastoma (Y79 and patient derived cells), hepatocellular carcinoma (Hep3B cells), head and neck cancer (UM-SCC cells), and colangiocarcinoma (EGI-1 cells) [ 6 , 14 , 15 , 16 , 17 , 18 ]. The aim of our work is to investigate if Rig could represent an effective anticancer agent also in other type of tumor lines.…”

In Vitro Evaluation of Rigosertib Antitumoral and Radiosensitizing Effects against Human Cholangiocarcinoma Cells

“…Rig is a multi-kinase inhibitor that could be considered an alternative therapeutic option for different solid tumors and hematologic malignancies. Its efficacy against myelodysplastic syndrome, head and neck cancer, hepatocellular carcinoma, retinoblastoma, and glioblastoma has already been demonstrated [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Moreover, on the website (July 2021) it is possible to highlight that Rigosertib is involved in various clinical trials.…”

Genome maintenance in retinoblastoma: Implications for therapeutic vulnerabilities (Review)

“…As is the case with other RB1-deficient cancer cells, primary RB tumors display high expression levels of several mitotic genes, including AURKB, polo-like kinase 1 (PLK1), mitotic arrest deficient 2 like 1 and BUB1 mitotic checkpoint serine/threonine kinase (43,44,89,90). Two recent studies have demonstrated that pharmacological inhibition of AURKB and PLK1 in RB cells resulted in cell cycle arrest and increased apoptosis, whereas the effects of the inhibitors on a nontumoral retinal pigment epithelial cell line (ARPE-19) were negligible under identical conditions, which was indicative of a higher sensitivity of RB cells to these inhibitors (89,91). Although both studies have not examined whether inhibition of these upregulated mitotic kinases causes chromosomal aberrations that may eventually lead to cell death, the results support the possibility that cancer cells with hyperactive mitotic checkpoint signaling due to RB1 loss might depend on AURKB and PLK1 for efficient mitotic exit and survival, establishing a synthetic lethal relationship with RB1 deficiency upon their inhibition.…”