MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma

• Published in: PloS one Vol. 9; no. 9; p. e105919
• Main Authors: Kanteti, Rajani, Dhanasingh, Immanuel, Kawada, Ichiro, Lennon, Frances E, Arif, Qudsia, Bueno, Raphael, Hasina, Rifat, Husain, Aliya N, Vigneswaran, Wickii, Seiwert, Tanguy, Kindler, Hedy L, Salgia, Ravi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.09.2014; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Biology and Life Sciences; Breast cancer; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer therapies; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Combinatorial analysis; Drug development; Drug Synergism; Drugs; Epidermal growth factor; Female; Hematology; Humans; Imidazoles - pharmacology; Immunoglobulins; Inhibitors; Intracellular signalling; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; MAP kinase; Medical prognosis; Medicine and Health Sciences; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - genetics; Mesothelioma, Malignant; Mice; Mice, Nude; Mutation; Oncology; Pathology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Phosphorylation - drug effects; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; PTEN Phosphohydrolase - metabolism; Pyrimidines - pharmacology; Pyrrolidinones - pharmacology; Quinolines - pharmacology; Studies; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors; Wound healing; Wound Healing - drug effects; Wound Healing - genetics; Xenograft Model Antitumor Assays; Xenografts; United States > US; Illinois; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0105919

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.