biostudies-literatureWong RACancer Research UKChildren's Tumor Samuel Waxman Cancer Research Foundation Evelyn and Mattie AndersonNCI NIH HHSNINDS NIH HHSNIH709-718https://www.ebi.ac.uk/biostudies/studies/S-EPMC7024655biostudies-literatureUnknown80(4)The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitorCancer researchCooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma.PMC7024655P50 CA097257A28592U01CA217864P30 CA082103R01 CA221969P50CA097257R01NS091620P30CA82103CSC201806370104R01CA221969U01 CA176287R01 NS091620U01CA176287U01 CA217864Haas-Kogan DALu MAn ZWong RALuo XPhillips JJShokat KMWeiss WAFan QWfalseCooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma.The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitor2020-01-01T00:00:00Z2020 Feb2025-04-26T00:34:28.734Z2025-04-06T09:45:27.555ZS-EPMC70246553180664110.1158/0008-5472.CAN-18-280810.1158/0008-5472.can-18-2808