The MEK/ERK Network as a Therapeutic Target in Human Cancer

Abstract

The RAS–RAF–MEK–ERK pathway is the most well-studied of the MAPK cascades and is critical for cell proliferation, differentiation, and survival. Abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins, RAS and RAF, are responsible for a significant fraction of human cancers and nearly all cutaneous melanomas. Activation of receptor tyrosine kinases by growth factors and various extracellular signals leads to the sequential activation of RAS, RAF, MEK, and finally ERK, which activates numerous transcription factors and facilitates oncogenesis in the case of aberrant pathway activation. While extensive studies have worked to elucidate the activation mechanisms and structural components of upstream MAPK components, comparatively less attention has been directed toward the kinases, MEK and ERK, due to the infrequency of oncogenic-activating mutations in these kinases. However, acquired drug resistance has become a major issue in the treatment of RAS- and RAF-mutated cancers. Targeting the terminal kinases in the MAPK cascade has shown promise for overcoming many of these resistance mechanisms and improving treatment options for patients with MAPK-aberrant cancers. Here, we will describe the role of MEK and ERK in MAPK signaling and summarize the current understanding of their interaction and activation mechanisms. We will also discuss existing approaches for targeting MEK and ERK, and the benefits of alternative strategies. Areas requiring further exploration will be highlighted to guide future research endeavors and aid in the development of alternative therapeutic strategies to combat surmounting drug resistance in treating MAPK-mediated cancers. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/3/361/F1.large.jpg.

MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

“…RAF kinase inhibitor protein (RKIP) is also an endogenous inhibitor of the MAPK/ERK signaling pathway via the suppression of MEK activation and phosphorylation by RAF. RKIP dissociates a RAF-MEK complex and behaves as a competitive inhibitor of MEK phosphorylation [ 33 ]. Thus, loss of RKIP results in abnormal activation of the MAPK/ERK pathway, and reduced RKIP expression has been observed in a variety of human cancers [ 7 , 34 ].…”

“…Although there are currently no FDA-approved inhibitors targeting ERK, the recognition that ERK reactivation arises in resistant cancers following prolonged treatment with RAF and MEK inhibitors has generated renewed interest in targeting ERK (see Section 2.7 ). Selective ERK1/2 inhibitors, including BVD-523, LY3214996, and ASTX-029, are currently under preclinical and clinical evaluation for various solid cancers with RAS or RAF mutations [ 33 , 139 , 146 , 147 , 148 ]. In particular, BVD-523 showed anti-proliferative activity in cell lines of colorectal and pancreatic cancers with B-RAF and K-RAS mutations, respectively [ 149 , 150 ].…”

Cancer nanotechnology: current status and perspectives

“…Protein synthesis, glucose metabolism, and other key components of cell survival are often hyper-activated in the PI3K/Akt/mTOR pathways, often re-routing signals in response to initial therapies [100]. The RAS/RAF/ MEK/ERK pathway initiates cell proliferation, differentiation, and development, thus multiple mutations are commonly found here across many cancer types [101,102]. Mutation in RAS proteins is the one of the most commonly found in human cancers, and Sotorasib is the first KRAS targeting drug to receive FDA approval [103,104].…”

Integrative Pan-cancer Analysis of MEK1 Aberrations and the Potential Clinical Implications

“…MEK1 is regarded as an effective therapeutic target and plays a vital role in oncogenesis processes 6 . MEK1 can be considered to be an oncogene, resulting in a series of tumorigenesis and alloplasia.…”