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.

SUBMITTER: Barbosa R 

PROVIDER: S-EPMC7925338 | biostudies-literature |

REPOSITORIES: biostudies-literature