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

Clin Cancer Res 2013 Oct 12;19(20):5722-32. Epub 2013 Sep 12.

Authors' Affiliations: Laboratory of Molecular Pathology, Ludwig Institute for Cancer Research; Moores Cancer Center; University of California San Diego, La Jolla; Celgene Corporation, San Diego; Department of Neurological Surgery and Brain Tumor Research Center, University of California at San Francisco, San Francisco; California Institute of Technology, Pasadena; Henry Singleton Brain Tumor Program; Jonsson Comprehensive Cancer Center; Department of Neurology, David Geffen UCLA School of Medicine; Department of Molecular and Medical Pharmacology; UCLA Medical Scientist Training Program, University of California, Los Angeles, Los Angeles, California; Celgene Corporation, Summit, New Jersey; Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital, Columbus, Ohio; Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Verona, Italy; INSERM; Metabolomics Platform, Institut Gustave Roussy, Villejuif; Université Paris Descartes/Sorbonne Paris Cité; Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers; and Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-13-0527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815450PMC
October 2013
78 Reads

Publication Analysis

Top Keywords

cc214-1 cc214-2
16
kinase inhibitors
16
mtor kinase
16
inhibitors cc214-1
12
cell death
8
vitro vivo
8
autophagy preventing
8
pharmacologic strategy
8
cc214 compounds
8
tumor cell
8
mtor
7
glioblastoma
5
cc214-1
5
cc214-2
5
novel single-cell
4
growth novel
4
cc214-2-induced cell
4
glioblastoma growth
4
signaling blocking
4
blocking glioblastoma
4

Altmetric Statistics

Similar Publications