Dual PI3K/AKT and CDK4/6 inhibition reveals selective sensitivity in an SHH medulloblastoma stem cell model.

Abstract

Medulloblastoma (MB) is a brain tumor for which current treatments cause serious side effects and are not curative for all patients, highlighting the need for more effective and brain-protecting therapies. Recently, we combined phosphoinositide 3-kinase (PI3K) inhibitor (BYL719), fibroblast growth factor receptor (FGFR) inhibitor (JNJ-42756493) and cyclin-dependent kinase (CDK)4/6 inhibitor (PD-0332991) in MB cell lines, and discovered synergistic effects. In the current study, we investigate the most efficient therapies in a normal/tumorigenic neural stem cell model. A sonic hedgehog (SHH)-MB model, including a Gorlin syndrome patient neuroepithelial stem cell line (NES) and its tumor derivative (tNES), was used to evaluate single and combined treatments of PI3K, AKT, FGFR, and CDK4/6 inhibitors (BYL719, AZD5363, JNJ-42756493, and PD-0332991, respectively). Effects on viability, cell confluence and apoptosis were tested on NES and tNES cells cultured as 2D monolayers and 3D spheroids. We found that 2D tNES cells were generally more sensitive to the inhibitory effects of both single and combination treatments compared to 2D NES cells. In the 3D setting, all single drugs were more effective against tNES than NES, except for JNJ-42756493, which showed the opposite trend. Drug combinations in 3D cultures generally resulted in synergistic or additive effects on cell viability in NES and tNES. This study illustrates that single and combined administrations of PI3K, FGFR, CDK4/6, and AKT inhibitors in a NES/tNES model have dose-dependent and additive/synergistic anti-MB activity impacting tumor growth. Their effects on tNES cells were generally more pronounced than on NES; however, the difference in proliferative capacity between the cells should be considered.