RRC ID 37064
Author Echeverry N, Ziltener G, Barbone D, Weder W, Stahel RA, Broaddus VC, Felley-Bosco E.
Title Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.
Journal Cell Death Dis
Abstract Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.
Volume 6
Pages e1757
Published 2015-5-7
DOI 10.1038/cddis.2015.124
PII cddis2015124
PMID 25950487
PMC PMC4669703
MeSH Autophagy / drug effects Bridged Bicyclo Compounds, Heterocyclic / pharmacology* Cell Proliferation / drug effects Drug Synergism Humans Imidazoles / pharmacology* Lung Neoplasms / drug therapy* Lung Neoplasms / metabolism* Lung Neoplasms / pathology Mesothelioma / drug therapy* Mesothelioma / metabolism* Mesothelioma / pathology Phosphatidylinositol 3-Kinases / antagonists & inhibitors* Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Pleural Neoplasms / drug therapy* Pleural Neoplasms / metabolism Pleural Neoplasms / pathology Protein Kinase Inhibitors / pharmacology Pyrimidines / pharmacology* Quinolines / pharmacology* Signal Transduction TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / metabolism
IF 5.959
Times Cited 7
Human and Animal Cells