Mesothelioma is a chemotherapy-resistant neoplasm, as is evident in the dismal survival for patients with this asbestos-associated disease. Conventional chemotherapies and radiation therapy have only limited efficacy, and improved survival will require development of novel and more effective pharmacological interventions. Although p53 genomic mutations are uncommon in mesothelioma, we hypothesized that functional p53 inactivation (resulting from NF2-dysregulated FAK activation) might be a frequent event. Using proteomic methods, with tandem mass spectrometry analyses of mesotheliomas after double immuno-affinity purifications for p53 and phosphotyrosine, we find that FAK is consitutively activated in 10 of 10 mesothelioma cell lines and 9 of 9 mesothelioma surgical specimens, and associated with p53 in 6 of 6 mesothelioma cell lines. In four mesotheliomas with non-mutant p53, FAK silencing by lentiviral short hairpin RNA (shRNA) induced expression and phosphorylation of p53 at Ser15. However, FAK regulation of mesothelioma proliferation was not restricted to p53-dependent pathways, as demonstrated by immunoblots after FAK knockdown in JMN1B mesothelioma cells, which have mutant/inactivated p53, compared to MESO924, MESO257, MESO296, and MESO428 cells, which have nonmutant p53. Additive effects were obtained through a coordinated attack on p53, as demonstrated by immunoblots, cell viability and cell cycle analyses, showing that FAK knockdown and MDM2 inhibition (nutlin-3) induced greater p53 expression, cell apoptosis, anti-proliferative effects and cell cycle arrest, compared to either intervention alone. These findings highlight novel therapeutic opportunities in mesothelioma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5031.