Wild-type TP53 defined gamma-secretase inhibitor sensitivity and synergistic activity with doxorubicin in GSCs.

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Aggressive surgical resection plus radiotherapy and temozolomide have prolonged patients' median survival to only 14.6 months. Therefore, there is a critical need to develop novel therapeutic strategies for GBM. In this study, we evaluated the effect of NOTCH signaling intervention by gamma-secretase inhibitors (GSIs) on glioma sphere-forming cells (GSCs). GSI sensitivity exhibited remarkable selectivity among wild-type TP53 (wt-p53) GSCs. GSIs significantly impaired the sphere formation of GSCs harboring wt-p53. We also identified a concurrence between GSI sensitivity, NOTCH1 expression, and wt-p53 activity in GSCs. Through a series of gene editing and drug treatment experiments, we found that wt-p53 did not modulate NOTCH1 pathway, whereas NOTCH1 signaling positively regulated wt-p53 expression and activity in GSCs. Finally, GSIs (targeting NOTCH signaling) synergized with doxorubicin (activating wt-p53) to inhibit proliferation and induce apoptosis in wt-p53 GSCs. Taken together, we identified wt-p53 as a potential marker for GSI sensitivity in GSCs. Combining GSI with doxorubicin synergistically inhibited the proliferation and survival of GSCs harboring wt-p53.