Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer

摘要

Abstract Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and cross-talk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notchl-4) and five ligands (DLL1, 3-4, Jagged 1-2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Because the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA-approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK-0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway. Background One hundred years ago, John S. Dexter observed serrations on the wing margin in Drosophila melanogaster (1). Decades later, Artavanis-Tsakonas and Young independently cloned the Notch receptor (2). The Notch signaling pathway is a highly conserved pathway among species (Fig. 1). In mammals, four type I trans-membrane Notch receptors (Notch 1-4) are synthesized. After cleavage at the SI site in the Golgi apparatus by a furin-like convertase, (3) it becomes glycosylated by O-fucosyltransferase (4, 5) and Fringe family N-acetylglucosaminidyl transferases (6); the processed heterodimers reassemble on the cellular membrane (7). The extracellular subunits, ofNotchl and 2, both have 36 EGF repeats; Notch3 and Notch4 have 34 and 29 repeats, respectively, which correlate with affinity for their respective ligands (8). In addition, the receptor contains a negative regulatory region composed of three cysteine-rich Linl2/Notch repeats and a C-terminal region (9,10). The other primary difference between the receptors rests within the transactivation domain (TAD) with either strong (Notchl), weak (Notch 2), or absent (Notch4) TAD (11). The Notch3 TAD is specific to activation of the hes5 promoter (12).