Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy

Abstract

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non-ATPcompetitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation.

Identification of Siah-interacting protein as a potential regulator of apoptosis and curcumin resistance

“…Besides, SIP has been found to interact with ERK1/2 and downregulate ERK activity (Kilanczyk et al, 2009). Furthermore, suppression of the ERK-involved pathway sensitizes cancer cells to apoptosis (Tran et al, 2001;Wu et al, 2004) and a series of inhibitors targeting ERK pathway have been identified as potential anti-cancer drugs (Daouti et al, 2009). It has also been shown that SIP serves as a molecular bridge between Siah-1 and Skp1 proteins, and forms a ubiquitin ligase complex together with Ebi and in turn promotes b-catenin degradation.…”

Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models

“…Both agents have shown some clinical benefits including partial response and stable disease, but have also revealed potential safety issues that were not known to be mechanism or chemo-type related (15,16). We have identified a new class of MEK inhibitors with a novel structure and a unique mechanism of action that may offer differential clinical benefit in cancer patients (17). Many challenges remain in the development of MEK inhibitors: (a) the selection of the most responsive patient population; (b) the use of biochemical markers for early proof of mechanism of action and to define an optimal dose regimen for target inhibition; (c) the use of surrogate markers to predict early response; and (d) the selection of optimal combination partners and regimens for rational combination therapy.…”

“…Recently, we have reported a new class of MEK inhibitors with novel chemical structure and mechanism of action (17). RO5068760 belongs to this class and exhibits a unique mode of MAPK signal blockade.…”

“…Upon compound treatment at various concentrations, p-ERK, cyclin D1, and p27 levels were analyzed by Western blot analysis, and cell proliferation/growth was analyzed by MTT as described previously (17).…”

“…Efficacy data were graphically represented as the mean tumor volume ± SEM. Tumor volume (in cubic millimeters) was calculated as described previously (17). Statistical analysis was determined by Mann-Whitney rank-sum test, one-way ANOVA, and post hoc Bonferroni t test (SigmaStat, version 2.0).…”