Abstract C164: Targeting receptor tyrosine kinases and their downstream signaling pathways in human schwannoma

<jats:title>Abstract</jats:title> <jats:p>Merlin-deficient tumors of the nervous system are common. The most frequent ones are schwannomas and meningiomas. Classical chemotherapeutic treatments are not effective and surgery/radiosurgery leave patients with considerable morbidity. Therefore there is a need for new effective and systemic treatments. Thus, our goal is to analyze schwannomas pathobiology to define new therapeutic targets in order to develop effective treatments for those tumors.</jats:p> <jats:p>We have previously observed overexpression/activation of platelet-derived growth factor receptor beta (PDGFRβ) in human primary schwannoma cells leading to strong activation of Raf/MEK1/2/ERK1/2 and AKT pathways, and enhanced cell proliferation. These effects were completely inhibited by commercially available Raf/PDGFR inhibitor sorafenib (Bay 43-9006; Bayer Pharmaceuticals). Although sorafenib could be a promising drug for the treatment of schwannomas, the benign character of those tumors would require long-term therapy which may result in the development of side effects in some patients. Thus, alternative drugs inhibiting PDGFR signaling may be necessary. Moreover, in addition to PDGFR, aberrant activation of other receptor tyrosine kinases (RTKs) such as EGFR and ErbB2, have also been reported in schwannoma.</jats:p> <jats:p>Thus, PDGFR, EGFR and ErbB2 and their downstream signaling pathways ERK1/2 and AKT may represent attractive therapeutic targets in schwannoma. Although several novel agents targeting RTKs and their downstream signaling pathways are under clinical investigation, those drugs have not been evaluated for schwannoma. Thus, using our human in vitro schwannoma model, we have tested additional inhibitors of PDGFR imatinib and nilotinib (Novartis), EGFR/ErbB2 inhibitor lapatinib (GlaxoSmithKline) and MEK1/2 inhibitor AZD6244 (ARRY-142886; Astra Zeneca).</jats:p> <jats:p>Using western blotting and proliferation assays we have shown that PDGFR inhibitors imatinib and nilotinib efficiently inhibited PDGF-DD mediated ERK1/2 and AKT activation/phosphorylation and cell proliferation. Similarly, EGFR/ErbB2 inhibitor lapatinib efficiently inhibited heregulin mediated activation/phosphorylation of ErbB2, ERK1/2, AKT and S6 ribosomal protein and cell proliferation. The expression of anti-apoptotic protein survivin was also decreased. MEK1/2 inhibitor AZD6244, was also very effective abolishing PDGFRβ mediated ERK1/2 activation and cell proliferation. In summary, imatinib, nilotinib, lapatinib and AZD6244 effectively inhibited signaling pathways involved in enhanced schwannoma proliferation and survival, suggesting that those agents used separately or in combination, could be promising drug candidates for schwannoma treatment. Therefore, next approach will be the translation of our in vitro studies into a clinical setting. Those drugs are under investigation and have been successfully evaluated in both Phase I and II studies, so the re-profiling of these drugs should be straightforward.</jats:p> <jats:p>Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C164.</jats:p>