Abstract 2523: BRAF is not the only predictor of sensitivity in vitro and in vivo for TAK-733, a selective potent inhibitor of MEK1/2

Abstract

Abstract MEK has emerged as an attractive target for pharmacologic intervention in cancer as the RAS/RAF/MEK/ERK cascade has proven to play a central role in the signaling required for cellular transformation and proliferation. Inhibition of MEK impacts a diverse array of additional cellular events, including differentiation, apoptosis, and angiogenesis. Identification of an orally active inhibitor of MEK which shows significant efficacy as a mono-therapy for the treatment of cancer would be ideal. TAK-733 is a potent non-ATP competitive allosteric inhibitor of MEK1/2 with IC50 values for the inhibition of MEK1/2 signaling of 2-5 nM at high (400 μM) and low (10 μM) ATP concentrations. TAK-733 was selective for mammalian MEK-1/2 in a panel of 71 enzyme assays. These included phosphodiesterases, 17 kinases (IC50 values >25 µM), cyclases, and 14 other enzymes (IC50 values >10 µM). Using an MTS (a tetrazolium salt) viability assay, TAK-733 was found to inhibit proliferation of numerous cancer cell lines expressing BRAF, KRAS, NRAS, PI3K, MEK1, EGFR mutations, cMET amplification, and wild type MAPK signaling with EC50 values ranging from 2 to 90 nM. A quantitative PK/PD relationship was established in the HT-29 human colorectal carcinoma murine xenograft model. This model showed a range of PD activity (ie, from no effect to maximum effect) which correlated well with tumor and plasma TAK-733 concentrations. The relationship between TAK-733 plasma concentration (PK) and target modulation (PD) was evaluated by modeling percent inhibition of tumor ERK phosphorylation and plasma TAK-733 concentrations at 4 hours postdose, using an inhibitory sigmoidal concentration response model. The plasma EC50 was calculated to be 45 ng/mL. TAK-733 exhibited broad-spectrum in vivo antitumor activity against a panel of human tumor xenografts with and without mutations in the MAPK pathway. These xenografts were of colon (COLO 205/ BRAF V600E and HT-29/ BRAF V600E/PI3K P449T), NSCLC (A549/ KRAS G12S, PC-9/ EGFRΔE746-A750, NCI-H1975/ EGFR L858R T790M), AML (HL-60/ NRAS), cholangio-carcinoma (EGI-1/ KRAS G12D) and melanoma (A375/ BRAF V600E) origins. A high incidence of tumor regressions was observed in this collection of cancer models. Collectively, preclinical pharmacology studies indicate TAK-733 is a specific inhibitor of MEK with the potential to significantly impair growth of a large number of cancers relying on the MAPK signaling cascade for growth and survival. and provides a strong rationale for study of this agent in clinical trials. 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 2523.