Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer

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 (Notch1-4) 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.

Figure 1

Notch receptors (Notch1-4) and ligands (DLL1, 3 and 4, Jagged 1-2) are expressed in tumor, normal, and endothelial cells. After ligand binding, the ICN is generated after cleavage events by ADAM/TACE proteases and γ-secretase. The ICN travels into the nucleus, interacts with multiple transcriptional regulators including CSL, displaces CoR, and recruits MAML to activate transcription of target genes. Potential cancer therapeutics that target Notch signaling include antibodies, peptides, miRNAs, TACE inhibitors, and GSIs. Notch can function as a tumor suppressor or is oncogenic and activate/inhibit different downstream targets depending on the malignancy and microenvironment.

Figure 2

Aberrant Notch signaling occurs in a wide variety of solid and hematologic malignancies, and its role may be oncogenic or tumor suppressive depending on the tissue type and cellular context.