Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin).
In this review, we summarize the current knowledge of molecular events triggered by <i>NF2</i>/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas.
NF2 mutations and/or Merlin inactivation are also seen in other cancers including some mesothelioma, breast cancer, colorectal carcinoma, melanoma and glioblastoma.
In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6).
Loss of merlin, a product of the neurofibromatosis 2 tumor suppressor gene, is being evaluated as a biomarker for FAK inhibitor sensitivity in mesothelioma.
Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma.
Inactivating mutations of the neurofibromatosis type 2 (NF2) tumor suppressor gene merlin have been described in nearly 60% of primary malignant mesothelioma and in approximately 20% of the mesothelioma cell lines.
The NF2 gene is also implicated in the development of sporadic schwannomas and meningiomas, as well as tumor types seemingly unrelated to the NF2 disorder, such as malignant mesotheliomas.
In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2(KO3/+)), after intraperitoneal inoculation of crocidolite fibres.
Immunohistochemical analysis of the mesothelioma confirmed loss of expression of the NF2 protein, and comparative genomic hybridization revealed losses of chromosomes 14, 15, and 22, and gain of 7.
Furthermore, malignant human tumors seemingly unrelated to the NF2 syndrome, such as neural crest-derived malignant melanomas, as well as malignant mesotheliomas (a pleural mesoderm-derived tumor), have also been found to be frequently mutated or deleted in the NF2 locus, suggesting a broader role for the NF2 gene in the initiation and progression of human neoplasms.