The mTOR kinase inhibitors, CC214-1 and CC214-2, preferentially block the growth of EGFRvIII-activated glioblastomas.

Abstract

PURPOSE:

mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.

EXPERIMENTAL DESIGN:

We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology-DNA Encoded Antibody Libraries-was used to identify mechanisms of resistance.

RESULTS:

Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2-induced cell death.

CONCLUSIONS:

These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it.

• Authors: Beatrice Gini, Ciro Zanca, Deliang Guo, Tomoo Matsutani, Kenta Masui, Shiro Ikegami, Huijun Yang, David Nathanson, Genaro R Villa, David Shackelford, Shaojun Zhu, Kazuhiro Tanaka, Ivan Babic, David Akhavan, Kelly Lin, Alvaro Assuncao, Yuchao Gu, Bruno Bonetti, Deborah S Mortensen, Shuichan Xu, Heather K Raymon, Webster K Cavenee, Frank B Furnari, C David James, Guido Kroemer, James R Heath, Kristen Hege, Rajesh Chopra, Timothy F Cloughesy, Paul S Mischel
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 20 Pg. 5722-32 (Oct 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24030701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2013 AACR.

Chemical References

• 6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo(4,5-b)pyrazin-2(3H)-one
• Antineoplastic Agents
• CC214-2
• Imidazoles
• Multiprotein Complexes
• Protein Kinase Inhibitors
• Pyrazines
• epidermal growth factor receptor VIII
• ErbB Receptors
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Autophagy (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics, metabolism)
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Imidazoles (pharmacology)
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Multiprotein Complexes (metabolism)
• PTEN Phosphohydrolase (metabolism)
• Protein Biosynthesis (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays