Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Abstract

The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

“…Some of these SYK inhibitors have been investigated in clinical trials including patients with autoimmune diseases and hematological malignancies [111,117], although several of the new and more potent inhibitors have so far not been evaluated in clinical trials. An interest in inhibition of the Ras-Raf-MEK-ERK pathway has also increased the last decade [137], and several inhibitors entering preclinical and clinical trials have emerged. MEK is probably the target where development has reached the farthest, and recently a clinical trial with the MEK inhibitor binimetinib was published [138].…”

“…MEK is probably the target where development has reached the farthest, and recently a clinical trial with the MEK inhibitor binimetinib was published [138]. Although the antileukemic effects of this inhibitor in monotherapy seem limited, this should further encourage investigating Ras-Raf-MEK-ERK in combination therapy, including inhibitors of the PI3K-Akt-mTOR pathway in AML [137,139].…”

Cutaneous Squamous Cell Carcinoma: From Biology to Therapy

“…The involvement of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways in cancer has led to the development of several inhibitors that target them [92,93]. In CSCC, a recent in vivo study demonstrated that the inhibition of MEK with trametinib and cobimetinib induces senescence in CSCC cell lines and reduces tumor growth in a mouse model [94].…”

Role of RASA1 in cancer: A review and update (Review)

“…The first protein kinase RAF in the RAS recruitment cascade is activated after GTP binding on the cell membrane through a series of complex processes including changing the phosphorylation state of the protein and binding with the skeleton protein and other kinases. The activated Raf kinase continues to phosphorylate and activate MAPKK protein kinase MEK1/2 and finally phosphorylates and activates ERK1/2, inducing abnormal proliferation, invasion, growth, and distant metastasis of malignant tumours ( 75 , 123 ). In addition, loss of RASA1 function can enhance RAS-ERK signal amplification ( 66 , 78 ).…”