eins involved in cell cycle and apoptosis regulation, and may lead to activation of the NF Brivanib VEGFR inhibitor κB transcription factor by phosphorylating and inactivating the inhibitor κB kinase . 4.1. Targeting MEK for cancer therapy The pivotal role played by the Raf/MEK/ERK module in the physiological regulation of many cellular processes, such as growth, proliferation, differentiation, survival, motility, and angiogenesis, provides the conceptual framework to understand the oncogenic potential of deranged signaling through this MAPK module. Indeed, many cellular oncogenes, such as growth factor receptors and Ras, critically rely on activation of the Raf/ MEK/ERK pathway to induce a transformed phenotype. In addition, members of this MAPK cascade, such as Raf and Mos, have been themselves identified as cellular oncogenes.
Although no naturally occurring MEK or ERK oncogenes have been identified, both proteins can efficiently transform mammalian cells to a neoplastic phenotype when expressed in a constitutively active form and disruption of their activation by pharmacological inhibitors severely impairs the transforming ability of many upstream acting cellular oncogenes. MLN8054 869363-13-3 As a result, constitutive MEK/ERK activation is detected in a significant proportion of a variety of human tumours, including breast, kidney, colon, pancreatic, thyroid and lung cancers, as well as GBM, and has recently emerged as a potential target for anticancer therapies.
Not only is constitutive activation of the MEK/ERK module frequently observed in experimental and human tumours, but rapid ERK inactivation, as opposed to slower decay of the activity of other MAPK families endowed with pro apoptotic activities such as the JNK and p38 families, may also be one of the factors underlying the massive apoptotic response elicited by several signal transduction targeted agents, a phaenomenon referred to asoncogene addiction or oncogenic shock. Indeed, it has been recently suggested that rapid diminution of phospho ERK, AKT, and STAT3/5 and delayed accumulation of the proapoptotic effector phospho p38 MAPK may substantially contribute to cell death following the pharmacologic or genetic inactivation of several oncogenes, such as Src, BCR ABL, and EGFR. These findings support the idea that the MEK/ERK signalling module may constitute a common therapeutic target downstream an array of diverse oncogenic genetic lesions.
Tortora et al. Page 9 Drug Resist Updat. Author manuscript, available in PMC 2008 September 23. NIH PA Author Manuscript NIH PA Author Manuscript NIH PA Author Manuscript As discussed above, the modular nature of the Raf/MEK/ERK cascade becomes less pleiotropic at the crossover point that is regulated by MEK. Indeed, no substrates for MEK have been identified other than ERK. This tight selectivity, coupled with the availability of monoclonal antibodies specific for the dually phosphorylated, active form of ERK, makes MEK inhibition exquisitely amenable to pharmacodynamic evaluation. In fact, phosphorylated ERK is the product of MEK activity and thus its ex vivo detection in tumour tissues could provide a direct measure of in vivo MEK inhibition. At the preclinical/early clinical stage, such pharmacodynamic assays are not only useful for optimizing the design of dosing regimens, but also offer the advantage of being able to correlate anti tumour efficacy with inhibition of the biochemical target. All these reasons make MEK a very attractive target for anticancer drug development