Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma

Federica Perrone, Genny Jocoll, Marzia Pennati, Marcello Deraco, Dario Baratti, Silvia Brich, Marta Orsenigo, Eva Tarantino, Cinzia De Marco, Claudia Bertan, Antonello Cabras, Rossella Bertulli, Marco Alessandro Pierotti, Nadia Zaffaroni, Silvana Pilotti

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2837-2848
Number of pages12
JournalEuropean Journal of Cancer
Volume46
Issue number15
DOIs
Publication statusPublished - Oct 2010

Keywords

  • Diffuse malignant peritoneal mesothelioma
  • EGFR
  • mTOR
  • p16
  • PDGFRB

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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