From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

Abstract

The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead.

Phenotype-based high-content chemical library screening identifies statins as inhibitors of in vivo lymphangiogenesis

“…Among the four major MAPK pathways, MEK1/2 has been shown to activate only ERK1/2, a major regulator of cell proliferation, survival, differentiation, motility, and angiogenesis that is activated by many growth factors and cytokines through activation of all three receptor classes (11). We found that the MEK inhibitor U0126, identified in our primary screen as a sprouting inhibitor, blocked lymphangiogenic sprouting in a dose-dependent manner with a minimal effective concentration of 1 μM.…”

“…Our finding that U0126 potently inhibited adult lymphangiogenesis in an established in vivo assay that partially mimics the tumor microenvironment, namely the mouse Matrigel plug assay loaded with VEGF, bFGF, and S1P, might provide an additional rationale for the use of MEK1/2 inhibitors in cancer therapy. As several major pharmaceutical companies are currently developing MEK1/2 inhibitors for anti-tumor therapy (11), it would be of interest to also investigate tumor lymphangiogenesis in these studies.…”

“…There are seven MAPKKs in humans that can be blocked with MEK inhibitors (11). Among the four major MAPK pathways, MEK1/2 has been shown to activate only ERK1/2, a major regulator of cell proliferation, survival, differentiation, motility, and angiogenesis that is activated by many growth factors and cytokines through activation of all three receptor classes (11).…”

“…We investigated whether its sprouting inhibitory effect is conveyed via inhibition of MEK1/2, its primary target, or by inhibition of MEK5 for which U0126 has a side-specificity at higher concentrations (11). Therefore, the MEK1/2 specific inhibitor RDEA 119, and the MEK5 specific inhibitor BIX 02189 were tested alone or in combination.…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…50 In lumenal cells, Rab11, Rabin8, and Rab8 colocalize when Rab11 is active. 51 53 and might serve to trigger large and sudden changes in vesicle trafficking associated with early epithelial scattering following HGF stimulation.…”