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.

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The mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 have been implicated in various physiological events, and specific targeting of these MAPKs could affect cell proliferation in many cell types. First, to evaluate the potential specific roles of these two MAPKs, we analyzed the mitogenic response in regenerating liver after partial hepatectomy (PH) and in primary culture of hepatocytes isolated from ERK1-deficient mice. We show that ERK1 knockout and wild-type (wt) cells replicate with the same kinetics after PH in liver, in vivo, and in primary cultures of hepatocytes, in vitro. Indeed, Cyclin D1 and Cdk1 appear to be expressed concomitantly in knockout and wt cells, highlighting that hepatocytes progress in the cell cycle independently of the presence of ERK1. Second, we specifically abolished ERK2 expression by RNA interference in mouse and rat hepatocytes. We investigated whether small interfering RNA (siRNA) targeting ERK2 could specifically inhibit its expression and interfere with the process of replication. In ERK1-deficient hepatocytes, silencing ERK2 expression by RNA interference and ERK2 activation by U0126 clearly demonstrate that DNA replication is regulated by an ERK2-dependent mechanism. Furthermore, in rat wt hepatocytes, whereas ERK2 targeting inhibits late G 1 and S phase progression, ERK1 silencing is devoid of any effect on cell proliferation, indicating that ERK1 cannot rescue ERK2 deficiency. Conclusion: Our results emphasize the importance of the MAPK cascade in hepatocyte replication and allow us to conclude that ERK2 is the key form involved in this regulation, in vivo and in vitro. T he Ras-dependent mitogen-activated protein kinase (MAPK) signaling cascade participates in control of cell fate, proliferation, and survival in various mammalian organs, including the liver. In adult rodent hepatocytes and regenerating liver, the MAPK MEK/ERK cascade plays a key role in regulating G 1 phase progression and consequently proliferation. 1,2 The ability to control precisely the order and timing of events is determinant for cell cycle regulation. 3,4 According to our previous data, the first part of G 1 is devoted to growth factor-dependent MEK/ERK-morphogenic events, whereas the mitogenic signal occurs in mid-G 1 phase. We showed that the sequential control mechanism of hepatocyte morphology and S phase entry by growth factor could involve successive activation of MEK2-ERK2 and then MEK1/MEK2-ERK1/ERK2 isoforms. 3 The process in early G 1 in relation to cytoskeletal reorganization induces hepatocyte spreading, making them permissive to DNA replication. In late G 1 phase, MEK1/MEK2-ERK1/ERK2 activation is associated with accumulation of Cyclin D1 and mitogen-dependent progression of hepatocytes to S phase. The central role of ERK2 in regulation was highlighted by the observation that ERK2 was preferentially activated in early and midlate G 1 phase. However, although ERK1 was slightly expressed and phosphorylated in early G 1 , a gradual