Malignant mesothelioma (MM) is a highly aggressive tumor characterized by local invasion of the pleura and metastasis, and is regarded as an almost incurable cancer with increasing incidence worldwide. Various cytokines and growth factors are reported to play important roles in the physiology of MM, possibly through MEK/ERK cascade. Thus, antitumor effects of TAK-733, a highly potent, selective, and non-ATP competitive inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), were investigated against MM cell lines, NCI-H226, MSTO-211H, NCI-H2052, NCI-H2452, and NCI-H28 harboring wild-type KRAS and BRAF and display moderate levels of basal ERK phosphorylation.

TAK-733 completely inhibited the ERK phosphorylation of 5 mesothelioma cell lines at 1-10 nM. TAK-733 also inhibited the proliferation of these cell lines in a dose dependent manner (IC50 = 4.9-240 nM). Treatment with TAK-733 clearly induced G1 cell cycle arrest with cyclin D1 down regulation and without up regulation of cleaved PARP in NCI-H226 and MSTO-211H cells. Once daily, oral administration of 1, 3, and 10 mg/kg TAK-733 potently inhibited the tumor growth of MSTO-211H xenograft in nude mice with T/C values of 31, 8, and −4% (T/C: treated per control on tumor volume growth over treatment period), respectively, with good tolerability. TAK-733 also showed potent antitumor activities against NCI-H226 and NCI-H2052 xenografts. Additionally, in an intrapleural MSTO-211H xenograft nude mouse model, daily oral administration of 3 and 10 mg/kg TAK-733 for 14 days significantly increased survival. These results demonstrate that TAK-733 is useful for the treatment of malignant mesothelioma with an activate MEK-ERK pathway.

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 2516.