Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma
| Autor: | Marcello Deraco, Marta Orsenigo, Rossella Bertulli, Eva Tarantino, Claudia Bertan, Nadia Zaffaroni, Genny Jocollè, Antonello Domenico Cabras, Silvia Brich, Cinzia De Marco, Dario Baratti, Silvana Pilotti, Marco A. Pierotti, Federica Perrone, Marzia Pennati |
|---|---|
| Přispěvatelé: | Perrone, Federica, Jocoll, Genny, Pennati, Marzia, Deraco, Marcello, Baratti, Dario, Brich, Silvia, Orsenigo, Marta, Tarantino, Eva, De Marco, Cinzia, Bertan, Claudia, Cabras, Antonello, Bertulli, Rossella, Pierotti, Marco Alessandro, Zaffaroni, Nadia, Pilotti, Silvana |
| Rok vydání: | 2010 |
| Předmět: |
Male
Mesothelioma Cancer Research Receptor Platelet-Derived Growth Factor alpha Diffuse malignant peritoneal mesothelioma DNA Mutational Analysis p16 Apoptosis medicine.disease_cause Receptor tyrosine kinase Platelet-Derived Growth Factor Receptor Beta Pleural Neoplasm biology Middle Aged Immunohistochemistry Platelet-Derived Growth Factor beta Receptor Protein-Tyrosine Kinase ErbB Receptors EGFR mTOR PDGFRB Adult Aged Female Genes p16 Humans Mutation Pleural Neoplasms Receptor Protein-Tyrosine Kinases Receptor Epidermal Growth Factor Receptor Platelet-Derived Growth Factor beta Oncology KRAS Human medicine.drug Receptor PDGFRA DNA Mutational Analysi Gefitinib medicine Protein kinase B PI3K/AKT/mTOR pathway Epidermal Growth Factor Platelet-Derived Growth Factor alpha Apoptosi Genes Cancer research biology.protein |
| Zdroj: | European journal of cancer (Oxford, England : 1990). 46(15) |
| ISSN: | 1879-0852 |
| Popis: | Our aim was to assess the activation profile of EGFR, PDGFRB and PDGFRA receptor tyrosine kinases (RTK) and their downstream effectors in a series of cryopreserved diffuse malignant peritoneal mesothelioma (DMPM) surgical specimens to discover the targets for drug inhibition. We also made a complementary analysis of the cytotoxic effects of some kinase inhibitors on the proliferation of the human peritoneal mesothelioma STO cell line. We found the expression/phosphorylation of EGFR and PDGFRB in most of the tumours, and PDGFRA activation in half. The expression of the cognate ligands TGF-α, PDGFB and PDGFA in the absence of RTK mutation and amplification suggested the presence of an autocrine/paracrine loop. There was also evidence of EGFR and PDGFRB co-activation. RTK downstream signalling analysis demonstrated the activation/expression of ERK1/2, AKT and mTOR, together with S6 and 4EBP1, in almost all the DMPMs. No KRAS/BRAF mutations, PI3KCA mutations/amplifications or PTEN inactivation were observed. Real-time polymerase chain reaction revealed the decreased expression of TSC1 c-DNA in half of the tumours. In vitro cytotoxicity studies showed the STO cell line to be resistant to gefitinib and sensitive to sequential treatment with RAD001 and sorafenib; these findings were consistent with the presence of the KRAS mutation G12D in these cells although it was not detectable in the original tumour. Our results highlight the ligand-dependent activation and co-activation of EGFR and PDGFRB, as well as a connection between these activated RTKs and the downstream mTOR pathway, thus supporting the role of combined treatment with RTK and mTOR inhibitors in DMPM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect