Molecular pathways: context-dependent approaches to Notch targeting as cancer therapy.

Recent high-throughput genomic sequencing studies of solid tumors, including head and neck squamous cell carcinoma (SCC), ovarian cancer, lung adenocarcinoma, glioblastoma, breast cancer, and lung SCC, have highlighted DNA mutation as a mechanism for aberrant Notch signaling. A primary challenge of targeting Notch for treatment of solid malignancies is determining whether Notch signaling is cancer promoting or tumor suppressing for a specific cancer. We compiled reported Notch receptor and ligand missense and nonsense mutations to glean insights into aberrant Notch signaling. Frequencies of coding mutations differed for the 4 NOTCH genes. A total of 4.7% of tumors harbored NOTCH1 missense or nonsense mutations. NOTCH2, and NOTCH3 had similar overall mutation rates of 1.5% and 1.3%, respectively, whereas NOTCH4 mutations were rarer. Notch ligand genes were rarely mutated. The combined mutation frequency and position spectra of the 4 Notch paralogs across the different cancers provide an opportunity to begin to illuminate the different contributions of each Notch paralog to each tumor type and to identify opportunities for therapeutic targeting. Notch signaling pathway activators and inhibitors are currently in early clinical development for treatment of solid malignancies. Defining the status and consequences of altered Notch signaling will be important for selection of appropriate treatment.