ku-0063794 and 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 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. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Brain Neoplasms; Cell Line, Tumor; ErbB Receptors; Erlotinib Hydrochloride; Female; Glioblastoma; Humans; Indoles; Janus Kinase 2; Mice; Morpholines; Protein Kinase C-alpha; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Amplification of the gene encoding the epidermal growth factor receptor (EGFR) occurs commonly in glioblastoma (GBM), leading to activation of downstream kinases, including phosphatidylinositol 3'-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). A serine-threonine kinase, mTOR controls cell growth by regulating mRNA translation, metabolism, and autophagy; acting as both a downstream effector and upstream regulator of PI3K. These signaling functions are distributed between at least two distinct complexes, mTORC1 and mTORC2 with respect to pathway specificity. We have investigated mTOR signaling in glioma cells with the allosteric mTORC1 inhibitor rapamycin, the mTORC1/2 inhibitor Ku-0063794, a dual PI3K/mTORC1/2 kinase inhibitor PI-103, and siRNA against raptor, rictor, or mTOR, and evaluated the value of mTOR inhibitors for the treatment of glioblastoma.

Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cell Line, Tumor; ErbB Receptors; Furans; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mechanistic Target of Rapamycin Complex 1; Morpholines; Multiprotein Complexes; Oncogene Protein v-akt; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proteins; Pyridines; Pyrimidines; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors