Exploratory analysis of activation of PTEN–PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM)

Cedrés, S.; Montero, M. Ángeles; Martı́nez, Pablo; Martinez, A.; Rodríguez-Freixinós, Víctor; Torrejon, Davis Y.; Gabaldon, Alejandra; Salcedo, Mayte; Cajal, Santiago Ramón y; Felip, Enriqueta

doi:10.1016/j.lungcan.2012.02.022

Cited by 61 publications

(54 citation statements)

References 49 publications

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“…Here, we have shown that key MET downstream signaling molecules including PI3K (p85 and p110α subunits), AKT and phospho-AKT are also expressed in majority of the cell lines tested. The archival human MPM tissue samples revealed significant overexpression of p-AKT, an indication of activated PI3K, a common feature shared by a variety of cancers [31]–[34].…”

Section: Discussionmentioning

confidence: 99%

MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

et al. 2014

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“…31 In other studies, the rate of mortality in patients with MM was increased 2.00-2.70-fold with NLR !5 versus <5; this difference was also statistically significant. 16,18 Cedre´s et al 20 found that NLR !5 was an independent prognostic factor in patients with MM. In the present study, the rate of mortality increased 1.67-fold in patients with MM who had an NLR of !3 compared with NLR <3; mean duration of survival was 10.5 months in those with an NLR !…”

Section: Discussionmentioning

confidence: 99%

The value of inflammatory parameters in the prognosis of malignant mesothelioma

et al. 2014

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Objective: This study investigated the relationship between potential prognostic parameters that may be associated with increased inflammation and survival in patients with malignant mesothelioma (MM). Methods: This retrospective study assessed potential prognostic parameters measured at the time of MM diagnosis. Data on asbestos exposure, histopathological subtype of MM and laboratory parameters were collected. Results: In 155 patients with MM (90 male), mean survival time was 13.9 months. In univariate analysis, age !60 years and neutrophil-to-lymphocyte ratio (NLR) !3 were associated with significantly shortened median survival times. In multivariate analysis, nonepithelial subtype, red cell distribution width (RDW) !20% and NLR !3 were associated with significantly shortened median survival times. Mortality rate was increased 2.77-, 1.67-and 1.52-fold in patients with RDW !20%, NLR !3 and nonepithelial subtype, respectively. Nonepithelial subtype, white blood cell count !11 200 ml and platelet-to-lymphocyte ratio !300 at baseline were associated with a heightened NLR value. Conclusions: The NLR and RDW were significant predictive factors for MM prognosis.

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“…Indeed, PI3K/mTOR signaling is activated in MPM [22] and a recent study has shown that patients with more than 1% of tumor cells positive for pS6 immunostaining, a biomarker of PI3K/mTOR activity, had worst overall survival [23]. Although it remains to be proven that pS6 positive cells correspond to the side population phenotype which is present in MPM, these observations render even more relevant therapeutic interventions blocking PI3K/mTOR to decrease ABCG2-dependent chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

“…PTEN-homozygous deletion has been observed only in a MPM cell line where inhibition of PI3K signaling by LY 294002 induced apoptosis per se [22] and loss of PTEN immunoreactivity is observed in 10-62% of MPM [23,26]. Other mechanisms of PTEN inactivation such as deficiency of PTEN pseudogene which acts as decoy for down-regulatory miRNA or by post-translational modification are possible [27,28] but remain to be investigated in MPM.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

Fischer¹,

Frei²,

Moura

et al. 2012

Lung Cancer

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Exploratory analysis of activation of PTEN–PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM)

Cited by 61 publications

References 49 publications

MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

The value of inflammatory parameters in the prognosis of malignant mesothelioma

Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy

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