title: Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors.
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.
authors.affiliation: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
authors.forename: N
authors.initials: N
authors.lastname: Echeverry
authors.affiliation: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Ziltener
authors.affiliation: Department of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
authors.forename: D
authors.initials: D
authors.lastname: Barbone
authors.affiliation: Division of Thoracic Surgery, University Hospital Zürich, Zürich, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Weder
authors.affiliation: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Stahel
authors.affiliation: Department of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
authors.forename: V C
authors.initials: VC
authors.lastname: Broaddus
authors.affiliation: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Felley-Bosco
mesh_terms: D001343:Autophagy / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; C546842:MTOR protein, human; C531198:dactolisib