Cancer Res. 2008 Jul 1;68(13):5236-45
Dissecting and targeting the growth factor-dependent and growth factor-independent
extracellular signal-regulated kinase pathway in human schwannoma.
Ammoun S, Flaiz C, Ristic N, Schuldt J, Hanemann CO.
Clinical Neurobiology, Peninsula College for Medicine and Dentistry, Research Way, Plymouth, United Kingdom.
are tumors of the nervous system that occur sporadically and in
patients with the cancer predisposition syndrome neurofibromatosis type
2 (NF2). Schwannomas and all NF2-related tumors are caused by loss of
the tumor suppressor merlin. Using our human in vitro model for
schwannoma, we analyzed extracellular signal-regulated kinase 1/2
(ERK1/2) and AKT signaling pathways, their upstream growth factor
receptors, and their role in schwannoma cell proliferation and adhesion
to find new systemic therapies for these tumors that, to date, are very
difficult to treat.
We show here that human primary schwannoma cells
show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2
pathway activity compared with healthy Schwann cells. Due to a strong
and prolonged activation of platelet-derived growth factor receptor
beta (PDGFRbeta), which is highly overexpressed, ERK1/2 and AKT
activation was further increased in schwannoma, leading to increased
proliferation. Using specific inhibitors, we discovered that ERK1/2
activation involves the integrin/focal adhesion kinase/Src/Ras
signaling cascades and PDGFRbeta-mediated ERK1/2 activation is
triggered through the phosphatidylinositol 3-kinase/protein kinase
C/Src/c-Raf pathway. Due to the complexity of signals leading to
schwannoma cell proliferation, potential new therapeutic agents should
target several signaling pathways.
The PDGFR and c-Raf inhibitor
sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for
treatment of advanced renal cell cancer, inhibits both basal and
PDGFRbeta-mediated ERK1/2 and AKT activity and decreases cell
proliferation in human schwannoma cells, suggesting that this drug
constitutes a promising tool to treat schwannomas. We conclude that our
schwannoma in vitro model can be used to screen for new therapeutic
targets in general and that sorafenib is possible candidate for future