Vestibular schwannomas (VS) arising sporadically or in patients with
neurofibromatosis type 2 (NF2) consistently lack expression of
Merlin, a
tumor suppressor. Conventional treatment options include surgery and
radiotherapy but there is no validated medical option. Recent evidence suggests that
Merlin deficiency may result in abnormal activation of
receptor tyrosine kinases (RTKs) and downstream signaling, promoting
tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such
therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream
kinases were validated immunohistochemically in corresponding
formalin-fixed,
paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2
kinase inhibitor
lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human
schwannoma model. EGFR/ErbB2 targeted
therapy with
lapatinib inhibited ErbB2 phosphorylation and
survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS.
Molecular targeted therapy with
lapatinib downregulates
survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with
lapatinib for the treatment of VS is currently underway.