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Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma.
- Source :
-
Cancer research [Cancer Res] 2020 Feb 15; Vol. 80 (4), pp. 709-718. Date of Electronic Publication: 2019 Dec 05. - Publication Year :
- 2020
-
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.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Acrylamides pharmacology
Acrylamides therapeutic use
Aniline Compounds pharmacology
Aniline Compounds therapeutic use
Animals
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Autophagy drug effects
Brain Neoplasms pathology
Cell Line, Tumor
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Erlotinib Hydrochloride pharmacology
Erlotinib Hydrochloride therapeutic use
Female
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 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
Antineoplastic Combined Chemotherapy Protocols pharmacology
Apoptosis drug effects
Brain Neoplasms drug therapy
Glioblastoma drug therapy
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 80
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 31806641
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-18-2808