Molecular Pathways: Targeting Mechanisms of Asbestos and Erionite Carcinogenesis in Mesothelioma. Clin Cancer Res.

University of Hawaii Cancer Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Clinical Cancer Research (Impact Factor: 8.19). 11/2011; 18(3):598-604. DOI: 10.1158/1078-0432.CCR-11-2259
Source: PubMed

ABSTRACT Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and ∼50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1β and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.

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Available from: Haining Yang, Jun 08, 2015
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    • "Given the heterogeneous and complex genetic nature of MPM [9] [10], many molecular aberrations underlying its progression and affecting clinical response have to be identified , while several trials of new biological agents in combination with pemetrexed and platinum are currently ongoing ( Previous studies supported preclinical investigations on key kinases that act as central regulators of the neoplastic process and are amenable to pharmacological inhibition. "
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    Current Drug Targets 12/2014; 15(14). DOI:10.2174/1389450116666141205160924 · 3.60 Impact Factor
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    • "However, the observed activation of multiple RTKs in mesothelioma suggests that transforming activity is dependent on coordinated activity of multiple tyrosine kinases (Kawaguchi et al, 2009; Menges et al, 2010; Perrone et al, 2010; Brevet et al, 2011; Ou et al, 2011b), and simultaneous inhibition of multiple kinases by cocktails of small-molecule kinase inhibitors or single-agent HSP90 inhibitors elicits compelling pro-apoptotic and anti-proliferative responses in mesothelioma preclinical models (Okamoto et al, 2008; Kawaguchi et al, 2009; Ou et al, 2011b). In addition to the evidence for PI3K/AKT and RAF/MEK/MAPK activation in mesothelioma initiation, there is likewise substantial evidence that these key signalling pathways are crucial in maintaining the transformed state, and in mesothelioma metastasis (Altomare et al, 2005; Cole et al, 2006; Patel et al, 2007; Jacobson et al, 2009; Suzuki et al, 2009; Shukla et al, 2011; Carbone and Yang, 2012; Cedres et al, 2012; Fischer et al, 2012; Menges et al, 2012; Miyoshi et al, 2012; Pinton et al, 2012). "
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    ABSTRACT: Background: Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis. Methods: Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations. Results: We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation. Conclusions: These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.
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