tailieunhanh - báo cáo khoa học: "From basic research to clinical development of MEK1/2 inhibitors for cancer therapy"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành y học dành cho các bạn tham khảo đề tài:From basic research to clinical development of MEK1/2 inhibitors for cancer therapy | Frémin and Meloche Journal of Hematology Oncology 2010 3 8 http content 3 1 8 JOURNAL OF HEMATOLOGY ONCOLOGY REVIEW Open Access From basic research to clinical development of MEK1 2 inhibitors for cancer therapy Christophe Fremin Sylvain Meloche Abstract The Ras-dependent Raf MEK ERK1 2 mitogen-activated protein MAP kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1 2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1 2 pathway. We then present the current state of clinical evaluation of MEK1 2 inhibitors in cancer and discuss challenges ahead. Introduction Human tumorigenesis is a multistep process during which accumulation of genetic and epigenetic alterations leads to the progressive transformation of a normal cell into a malignant cancer cell. During this process cancer cells acquire new capabilities hallmarks that enable them to escape from normal homeostatic regulatory defense mechanisms. These hallmarks are defined as self-sufficiency in growth signals insensitivity to antiproliferative signals evasion from apoptosis limitless replicative potential sustained angiogenesis and increased motility and invasiveness 1 . While the mechanisms by which cancer cells acquire these capabilities vary considerably between tumors of different types most if not all of these physiological changes involve alteration of signal transduction pathways. Among the signaling pathways most frequently dysregulated in human cancer is the Ras-Raf-MEK-extracellular signal-regulated kinase 1 and 2 ERK1 2 .