Mitogen activated protein (MAP) kinases include the extracellular signal regulated kinases 1 and 2 (ERK1 and ERK2). MAP kinases play a role in the regulation of biological processes including cell growth, proliferation, differentiation, inflammatory responses and programmed cell death. Unregulated activation of MAP kinases has been linked to cancer cell proliferation and tissue inflammation. Activation of ERK proteins often occurs through a process wherein a ligand-activated plasma membrane receptor facilitates the sequential activation of the Ras G-proteins, Raf kinases, and the MAP or ERK kinases-1 and 2 (MEK1/2), which are activators of ERK1 and ERK2.
Development of biomarkers for use in connection with anti-cancer chemotherapeutic agents has proven to be of enormous utility. For example, biomarkers may be employed to monitor, quickly and conveniently, the therapeutic effect of a given agent, for example, the effect of the inhibitor on the intracellular pathway it is targeting or the tumor it is treating. Biomarker genes that prove useful in the evaluation of a given agent often appear, at first glance, to be unrelated to the function of the molecular target of the agent. This makes the prediction of what biomarkers will be useful with a given agent difficult. For example, IL-8 is a pro-inflammatory cytokine whose upregulation is associated with various inflammatory disorders. Any prediction that IL-8 may be useful for monitoring the efficacy of, for example, an ERK inhibitor, based on knowledge held in the art, would have been unlikely.