Endogenous inhibitors of PP2A activate oncogenic and DNA damage response kinases in glioblastoma

Glioblastomas (GBMs) exhibit constitutive activation of oncogenic kinase signaling pathways, contributing to tumor aggressiveness and resistance to therapy. Kinase inhibitors have demonstrated limited efficacy against GBMs, primarily due to the tumors' ability to adapt to diverse stimuli and effectively rewiring critical downstream signaling networks. This remarkable adaptability underscores the pressing need for novel therapeutic strategies that sustain the inhibition of oncogenic kinase signaling in GBM. This study sought to elucidate the mechanisms by which GBMs maintain the constitutive activation of oncogenic kinase signaling under the surveillance of intact tumor suppressor protein phosphatase 2A (PP2A). We identify that GBMs inhibit PP2A activity through overexpression of endogenous inhibitors (EIPs), including ANP32A, CIP2A, and SET. Inhibition of these EIPs restores PP2A activity, disrupting oncogenic kinase activation and transcription factor signaling, reducing tumor formation. Furthermore, CRISPR-Cas9 EIP silencing enhances PP2A's ability to target DNA damage response kinases ATR and ATM, sensitizing tumors to radiation by impairing DNA repair and cell cycle checkpoint control. These findings reveal the therapeutic potential of activating PP2A in GBMs, both as a standalone strategy and in combination with radiation.