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MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma
No full textMalignant 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.</p
Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer
No full text
MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma
No full textMalignant 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.Version of Recor
MET inhibition alone or in combination with PI3K/mTOR dual inhibitors induces cell cycle arrest and apoptosis.
No full text<p>H2596 cells were treated with ARQ 197, GDC-0980, NVP-BEZ235 alone and in combination for 48 h. Cell cycle profile was determined using flow cytometry after staining with PI/RNase. <b>Fig.</b><b>A</b> shows the percentage of cells in G1, S, and G2/M phases was quantified and the results expressed as the mean ± SEM of four independent experiments. H2596 <b>(B)</b> and H513 <b>(C)</b> cells, were treated with ARQ 197, GDC-0980, NVP-BEZ235 alone and in combination for 48 h. Cell lysates were prepared and immunoblotted for total PARP, cleaved PARP, cyclin D1 and actin as a loading control. H2596 cells treated with ARQ 197, GDC-0980, NVP-BEZ235 alone and in combination for 48 h, the cells were then stained with Annexin V-FITC/PI and analyzed by flow cytometry. Results are expressed as mean percentage of apoptotic cells ± SEM of four independent experiments <b>(D)</b>.</p
IC<sub>50</sub> of Mesothelioma cell lines with MET and PI3K/mTOR inhibitors.
No full text<p>IC<sub>50</sub> of Mesothelioma cell lines with MET and PI3K/mTOR inhibitors.</p
Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma
No full textC. Elegans and Mutants With Chronic Nicotine Exposure as a Novel Model of Cancer Phenotype
No full textThis article provides evidence in support of C. elegans as initial in vivo model to study nicotine and its effects on oncogenic mutations identified in humans
Effect of combined MET and PI3K/mTOR inhibition on kinase activation profile and downstream signaling pathways in MPM.
No full text<p>H2596 and H513 cells were plated in 10 cm tissue culture plates overnight and next day treated with indicated inhibitors for 4 h. Phospho-AKT (p-AKT <sup>Ser473</sup>, p-AKT <sup>thr308</sup>), total AKT, p-S6K and total S6K were assessed in <b>(A)</b> H2596 and <b>(B)</b> H513 by immunoblotting. <b>(C)</b> H2596 cells were plated in 10 cm tissue culture plates overnight and next day treated with indicated inhibitors for 24 h. PIP3 content was measured via dot blot and densitometric analysis for each blot is shown.</p
