Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the <i>dl922-947</i> Oncolytic Virus in Malignant Mesothelioma Cell Lines

• Main Authors: Carmelina Antonella Iannuzzi, Paola Indovina, Iris Maria Forte, Sarah Di Somma, Anna Maria Malfitano, Martina Bruno, Giuseppe Portella, Francesca Pentimalli, Antonio Giordano
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: International Journal of Molecular Sciences
• Subjects: malignant mesothelioma; oncolytic adenovirus; <i>dl922-947</i>; WEE1; AZD1775; MK-1775
• Online Access: https://www.mdpi.com/1422-0067/21/19/7333
• ISSN: 1661-6596; 1422-0067

Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, for which no therapy proves to be effective. We have recently shown that the oncolytic adenovirus <i>dl922-947</i> had antitumor effects in MM cell lines and murine xenografts. Previous studies demonstrated that <i>dl922-947</i>-induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy. However, the cellular DNA damage response (DDR) can counteract this virus action. Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to <i>dl922-947</i>. Through cell viability assays, we found that AZD1775 synergized with <i>dl922-947</i> selectively in MM cell lines and increased <i>dl922-947</i>-induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation). Predictably, <i>dl922-947</i> and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (γ-H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1). <i>Dl922-947</i> also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation. This increase in phospho-CDK1 was effectively suppressed by AZD1775, thus suggesting that this compound could, indeed, abrogate the <i>dl922-947</i>-induced DNA damage checkpoint in MM cells. Overall, our data suggest that the <i>dl922-947</i>-AZD1775 combination could be a feasible strategy against MM.