TARGETING CANCER STEM CELLS WITH A CDK2 INHIBITOR IN GLIOBLASTOMA

Abstract Glioblastoma (GB) is the most common and aggressive adult brain tumor with no cure. Brain stem cells (BTSCs) are a rare population of self-renewing multipotent in GB that contribute to tumorigenesis, therapeutic resistance, tumour recurrence. Here, we report CDK2 inhibitor suppresses BTSCs via OSM/OSMR/STAT3 signalling pathway. To begin with, performed high throughput screening (HTS) ~8400 compounds including FDA-approved drugs patient derived human naturally harbour EGFRvIII mutation elevated STAT3 phosphorylation, search can suppress EGFRvIII/OSMR/STAT3 oncogenic The screen led identification panel CDK inhibitors possessed important characteristics a) ability cross blood-brain barrier mall molecular weights 277-566 kDa, b) low Topological Polar Surface Area (TPSA) 76-115 A°, c) number Hydrogen Bond Donors (HBDs) (1-4), d) cLogP values ranging from 2-4. Following counter screens, focused on significantly efficiently reduced OSM/OSMR activation. Importantly, found compound inhibited self-renewal growth subtype BTSCs. This research has future investigation vivo assessment this combination ionizing radiation chemotherapy preclinical models GB.