Targeting mitotic kinesin KIF20A: A differentiation-based therapeutic strategy for glioblastoma stem/progenitor cells.

Abstract

Glioblastoma multiforme (GBM) remains refractory to current treatment modalities. Differentiation-based approaches, which force cancer stem/progenitor cells to exit the cell cycle and adopt terminal fates, offer an alternative therapeutic strategy. Cell fate regulators operating during stem/progenitor cell divisions integrate proliferative and anti-proliferative cues and represent particularly attractive points of intervention. Here, we investigated the therapeutic potential of targeting mitotic kinesin KIF20A in GBM stem/progenitor cells. KIF20A is a crucial component of cytokinetic machinery and cooperates with a network of cell fate regulators to balance proliferative and differentiative divisions in neural stem/progenitor cells (NSPCs). Using complementary in vitro and in vivo models, including 2D cultures, 3D organoids, and intracranial xenografts, we show that inhibition of KIF20A drives cell cycle exit and induces a postmitotic/differentiated state in GBM stem/progenitor cells, resulting in a marked suppression of proliferation. Together, these findings establish KIF20A as a key vulnerability in GBM and a promising target for differentiation-based intervention.