Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma

Cancer Res. 2020 Feb 15;80(4):709-718. doi: 10.1158/0008-5472.CAN-18-2808. Epub 2019 Dec 5.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Acrylamides / therapeutic use
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects*
  • Autophagy / drug effects
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / pharmacology
  • Erlotinib Hydrochloride / therapeutic use
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / pathology
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Mice
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • Protein Kinase C-alpha / antagonists & inhibitors
  • Protein Kinase C-alpha / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Purines / pharmacology
  • Purines / therapeutic use
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • AZD 1480
  • Acrylamides
  • Aniline Compounds
  • Indoles
  • Morpholines
  • Protein Kinase Inhibitors
  • Purines
  • Pyrazoles
  • Pyrimidines
  • osimertinib
  • Ku 0063794
  • Erlotinib Hydrochloride
  • MTOR protein, human
  • EGFR protein, human
  • ErbB Receptors
  • JAK2 protein, human
  • Janus Kinase 2
  • TOR Serine-Threonine Kinases
  • PRKCA protein, human
  • Protein Kinase C-alpha
  • PP242
  • sapanisertib