Aurora Kinase A and B inhibition abrogates 'Neosis', a non-mitotic cell division of GBM residual cells and prevents GBM recurrence.

Abstract

Glioblastoma (GBM) has a dismal median survival of 15 months owing to therapy resistance and inevitable recurrence. Using our cellular models of GBM radiation resistance, we had shown that GBM recurrence is due to survival and proliferation of residual disease cells enriched in multinucleated giant cells (MNGCs). However, MNGC division mechanism remained elusive. Here, using live-cell imaging we found daughter cells emerge from MNGCs by cytoplasmic pinching. Lack of DNA condensation, absence of spindle poles and acto-myosin contractile ring in dividing-MNGCs confirmed non-mitotic division of MNGCs. Furthermore, MNGCs harboured DNA damage, senescence phenotype, repeated atypical division after radiation exposure, characteristics of unconventional division called 'Neosis'. Molecularly, WGCNA co-expression network analysis of RNA-Sequencing from parent, non-dividing MNGCs and dividing-MNGCs identified significantly high expression of aurora kinases (AurA and AurB) specifically in dividing-MNGCs. Pharmacological and genetic inhibition of aurora kinases abrogated MNGC neosis, preventing GBM recurrence in vitro and in vivo in an orthotopic GBM mouse model. Together, this study demonstrates that MNGCs divide by neosis, an atypical division mediated by AurA and AurB and identify aurora kinases as a potential molecular target to inhibit neosis and prevent GBM recurrence.