azd-6244 and Neurilemmoma

Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec(;) Novartis) and nilotinib (Tasigna(;) Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that  simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Humans; Imatinib Mesylate; Immunoblotting; MAP Kinase Signaling System; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Pyrimidines; Receptors, Platelet-Derived Growth Factor; Signal Transduction

Deficiency of the tumor suppressor merlin leads to the development of multiple tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas. Due to the benign character of these tumors, classical chemotherapy is ineffective. Current therapies, surgery, and radiosurgery are local and quite invasive, thus new systemic treatments are required. We have previously described the Raf/mitogen-activated kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway activation and its role in schwannoma growth. Here, we targeted MEK1/2 known as a convergence point for multiple cascades towards ERK1/2 activation and cell proliferation, using MEK1/2 inhibitor AZD6244 (ARRY-142886; Astra Zeneca). We show that AZD6244 at low concentration completely abolished platelet-derived growth factor-DD-mediated ERK1/2 activation and cell proliferation in human primary schwannoma cells. Moreover, this drug was not toxic for either schwannoma or Schwann cells and has been reported to be safe with tolerable side effects. Thus, AZD6244 can be considered as a drug candidate for schwannoma treatment.

Topics: Antineoplastic Agents; Benzimidazoles; Bromodeoxyuridine; Cell Proliferation; Cells, Cultured; Enzyme Inhibitors; Humans; Immunoblotting; Immunohistochemistry; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Neurilemmoma; Phosphorylation; Platelet-Derived Growth Factor; Schwann Cells