Identified Notch1 genetic alterations are presumed to be activating and are reported to include somatic frame shift (fs) mutations in the TAD and PEST domains (S2275fs and V2444fs, respectively) and non-synonymous substitutions in the heterodimerization region and TAD domain (D1643H and R2328W, respectively), and, importantly, are demonstrated to be susceptible to inhibition by GSIs DAPT and MRK-003 and, furthermore, required in driving sustained tumor cell survival [78], thus providing a rationalized framework for the devising of Notch1-targeting therapies. This evidence concerns the gene NOTCH1 and neoplasm.