Introduction

One of the hallmarks of the malignant phenotype is the ability of cells to grow in an autonomous manner with minimal cell death. This has been linked to diverse machinery of the proliferative and/or survival signaling pathways that become constitutively activated or deregulated in all human cancers. The proto-oncogenic driver mutations of Ras (H-, N-, K-ras, depending on tissue origin) or Raf gene are frequently tied to constitutive mitogen activated protein kinases (MAPK)/the extracellular signal regulated kinase (ERK1/2) signaling in a variety of tumors (Figure 9.1). Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, ERK1/2 inhibitors represent a desirable class of anti-neoplastic agents. Accumulating results have independently supported the promising anti-cancer effects of this class of inhibitor in numerous pre-clinical and clinical studies, i.e. CI-1040[1], selumetinib (AZD6244)[2–4], AS703026[5] and GSK1120212[6]. In fact, the MEK1/2 inhibitor CI-1040 (Pfizer) was the first signal transduction inhibitor tested in clinical trials in various advanced solid tumors[7]. Although no MEK1/2 inhibitors are approved for clinical use, kinase inhibitors that also inhibit Raf and VEGFR kinases (e.g. Sorafenib inhibiting multikinases)[8, 9] are successful anti-neoplastic agents against many types of cancer and FDA approved for the treatment of patients with unresectable hepatocellular carcinoma and advanced renal cell carcinoma [10, 11] (Figure 9.2). Such information support targeting this pathway, alone or in combination with other well-established growth and survival pathways, i.e. phosphoinositide 3-kinase (PI3K)/Akt/mTOR, STAT3, NFκB, heat shock proteins (Hsp90, Hsp70), histone deacetylases (HDAC), osteoblast (OB) as effective strategies across multiple cancers.