title: MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Rajani
authors.initials: R
authors.lastname: Kanteti
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Dhanasingh
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawada
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lennon
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Qudsia
authors.initials: Q
authors.lastname: Arif
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Rifat
authors.initials: R
authors.lastname: Hasina
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Aliya N
authors.initials: AN
authors.lastname: Husain
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Wickii
authors.initials: W
authors.lastname: Vigneswaran
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Seiwert
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.affiliation: Department of Hematology/Oncology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007093:Imidazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D011743:Pyrimidines; D011760:Pyrrolidinones; 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; C551661:ARQ 197; C546842:MTOR protein, human; C491743:MET protein, human; C494929:PTEN protein, human; C531198:dactolisib