Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy

Abstract

Introduction: The MAPK pathway comprises several key signaling components and phosphorylation events that play a role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. These pathways are considered potential therapeutic targets for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials.

Areas covered: The biological role of the RAS-MAPK pathway, the consequence of its disregulation and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway and the application and the results of various inhibitory molecules as anticancer agents in clinical trials.

Expert opinion: Inhibitors of MEK and particularly of RAF kinases have shown effectiveness in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.

Figure 1

Schematic representation of the MAPK cascade activation and potential cross talk signals. Growth factors binding, and causing activation of, tyrosine kinase receptors, activating mutations of BRAF and RAS, and additional external cell membrane stimuli may cause persistent activation of the MAPK cascade in human cancers. Numerous effectors signals converge on RAF, activated RAF phosphorylates MEK in the cytoplasm, which in turn phosphorylates ERKs that translocates to the nucleus where they phosphorylate and regulate various nuclear and cytoplasmic substrates involved in diverse cellular responses, such as cell proliferation, survival, differentiation, motility, and angiogenesis. RAS may cross-talk with different signalling pathways, e.g. PI3K, to enhance tumorigenesis in cancer cells.

Figure 2

Schema of the domain structure of human A-Raf, B-Raf, and C-Raf. The three mammalian RAF serine/threonine protein kinases, ranging from 70 to 100 kDa in size, mediate the transduction of proliferative and differentiative signals from cell surface receptors to the nucleus catalyzing the phosphorylation of hydroxyl groups on specific Ser and Thr residues. A-Raf gene (Location: Xp11.4-p11.2). This isoform is the weakest activator of MEK, and can only activate MEK1 but not MEK2. B-Raf gene (Location: 7q34); BRAF point mutations within the kinase domain of the protein occur in several tumor types including, melanomas, papillary thyroid and colorectal carcinomas. C-Raf gene (Location: 3p25); CRAF is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Among 3 RAF isoforms, BRAF displays the highest basal kinase activity. S, serine; T, threonine; Y, tyrosine: amino acid phosphorylation sites regulating the Raf kinases. Abbreviations: C, carboxyl terminus; N, amino terminus; RBD, Ras-binding domain; CRD, cysteine-rich domain; KSR, kinase suppressor of Ras; MEK, mitogen-activated protein kinase kinase; PAK, p21-activated kinase; PKA, protein kinase A; PKCα, protein kinase C alpha; SGK, steroid glucocorticoid kinase; Src, soluble nonreceptor tyrosine kinase.