Atypical teratoid rhabdoid tumors (ATRTs) are aggressive juvenile brain tumors with no current treatment options and a 12- to 18-month median survival rate. Previously, cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase linked in numerous malignancies, were identified as major drivers of tumorigenicity in ATRTs in genetic studies. Because a variety of cyclin-dependent kinases (CDKs) assist the effects of EZH2 and cyclin D1, the researchers wanted to see if targeting CDKs in ATRTs with the multi–CDK inhibitor TG02 could have therapeutic effects. For this study, they chose the human ATRT cell lines BT12, BT37, CHLA05, and CHLA06. Cell viability, proliferation, clonogenicity, and apoptosis were evaluated using Cell Counting Kit-8 assays, cell counting, clonogenic tests, and flow cytometry. The effects of TG02 coupled with radiation therapy (RT) or cisplatin were studied using similar approaches. They used software to construct synergism indices for TG02-cisplatin combination treatment.
In vitro, TG02 was found to inhibit ATRT cell growth by restricting cell proliferation, clonogenicity, and apoptosis. With nanomolar half-maximal effective concentration (EC50) values, TG02 reduced ATRT cell proliferation and decreased cell survival in a dose-dependent manner (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). 72 hours after treatment, TG02 (150 nM) significantly increased the proportion of apoptotic ATRT cells (TG02 8.50% vs. control 1.52 % apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs. control 15.36%, p < 0.0001). TG02 was found to be a strong radiosensitizer in ATRT cells in combination therapy trials (BT12 surviving fraction, RT 51.2% vs. RT + TG02 21.7%). Finally, software analysis revealed that TG02 and cisplatin operated synergistically against ATRT cells at nearly all therapeutic levels. They replicated findings in ATRT cell lines from all three molecular groupings. The findings of this study show that TG02 is an efficient ATRT inhibitor in vitro. Given the lack of standard ATRT therapy, the findings fill a gap in the market and promote continued research into TG02 as a viable therapeutic option for people suffering from this fatal condition.
Reference:thejns.org/pediatrics/view/journals/j-neurosurg-pediatr/28/6/article-p734.xml
