American Association for Cancer Research
00085472can182808-sup-208403_3_supp_5922772_q1jggg.pdf (20.6 MB)

Cooperative blockade of PKCα and JAK2 drives apoptosis in glioblastoma from Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma

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journal contribution
posted on 2023-03-31, 03:24 authored by Robyn A. Wong, Xujun Luo, Mimi Lu, Zhenyi An, Daphne A. Haas-Kogan, Joanna J. Phillips, Kevan M. Shokat, William A. Weiss, Qi Wen Fan

Supplementary Figure S1. PP242 induced apoptosis through a mitochondrial-dependent pathway. Supplementary Figure S2. PP242 showed potent blockade of p-MARCKS, but not p-STAT3Y705 in GBM6 cells. Supplementary Figure S3. Effects of PKC, JAK2, and mTOR inhibitors on cell proliferation and apoptosis. Supplementary Figure S4. Cooperative blockade of PKCα and JAK2 drives apoptosis. Supplementary Figure S5. Efficacy and tolerability of combination therapy in mice.



Cancer Research UK

Children's Tumor

Samuel Waxman Cancer Research Foundation

Evelyn and Mattie Anderson



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 inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.