PEST Domain Mutations in Notch Receptors Comprise an Oncogenic Driver Segment in Triple-Negative XXXX Sensitive to a y-Secretase Inhibitor.

@entity1 @entity0 @entity5 @entity7363 @entity125 @entity61117 @entity126
PURPOSE: To identify and characterize novel, activating mutations in Notch receptors in @entity0 and to determine response to the gamma secretase inhibitor (GSI) @entity61117 . EXPERIMENTAL DESIGN: We used several computational approaches, including novel algorithms, to analyze next-generation sequencing data and related omic datasets from The @entity5 (TCGA) @entity0 cohort. @entity1 -derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with @entity61117 . Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by @entity61117 . RESULTS: We identified mutations within and upstream of the PEST domains of @entity125 , @entity126 , and @entity7363 in the TCGA dataset. Mutations occurred via several genetic mechanisms and compromised the function of the PEST domain, a negative regulatory domain commonly mutated in other @entity5 . Focal amplifications of @entity126 and @entity7363 were also observed, as were heterodimerization or extracellular domain mutations at lower incidence. Mutations and amplifications often activated the Notch pathway as evidenced by increased expression of canonical Notch target genes, and functional mutations were significantly enriched in the triple-negative @entity0 subtype (TNBC). PDX models were also identified that harbored PEST domain mutations, and these models were highly sensitive to @entity61117 . CONCLUSIONS: This work suggests that Notch-altered @entity0 constitutes a bona fide oncogenic driver segment with the most common alteration being PEST domain mutations present in multiple Notch receptors. Importantly, functional studies suggest that this newly identified class can be targeted with Notch inhibitors, including GSIs. Clin Cancer Res; 21(6); 1487-96.   2015 AACR.
