# PEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a gamma-secretase inhibitor

Source: https://onco.cc/key-papers/paper-wang-notch-pest-mutations-tnbc-ccr-2015/  
OnCo record `paper-wang-notch-pest-mutations-tnbc-ccr-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Mutations that destroy the off-switch (PEST domain) of NOTCH1, NOTCH2 and NOTCH3, plus focal amplifications, cluster in triple-negative tumours in TCGA and made patient-derived tumours highly sensitive to a gamma-secretase inhibitor.

## Summary

Novel algorithms applied to TCGA breast cancer sequencing identified mutations within and upstream of the PEST domains of NOTCH1, NOTCH2 and NOTCH3, arising by several genetic mechanisms and compromising the negative regulatory domain, plus focal NOTCH2 and NOTCH3 amplifications and rarer heterodimerisation or extracellular domain mutations. Alterations activated canonical Notch targets and functional mutations were significantly enriched in TNBC. Patient-derived xenografts with PEST mutations were highly sensitive to PF-03084014.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Clinical Cancer Research
- Year: 2015
- DOI: 10.1158/1078-0432.CCR-14-1348
- Authors: Wang K, Zhang Q, Li D, et al.
- Findings: PEST-domain mutations across NOTCH1/2/3 and focal NOTCH2/3 amplifications enriched in TNBC.; PEST-mutant patient-derived xenografts responded to the gamma-secretase inhibitor PF-03084014.
- What it means: It widens the NOTCH driver segment beyond rearrangements to PEST mutations that ordinary DNA panels can report, the finding that fed NOTCH-mutant cohorts into basket trials.
- Caveats: Computational discovery with xenograft validation; no clinical response data.; Frequencies in the abstract are qualitative.

## Sources

- Wang et al., Clin Cancer Res 2015: PEST domain Notch mutations as a TNBC driver segment: https://doi.org/10.1158/1078-0432.CCR-14-1348
- PubMed: https://pubmed.ncbi.nlm.nih.gov/25564152/

## Connected records

- cancers: [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- targets: [Gamma-secretase (PSEN1)](https://onco.cc/targets/gamma-secretase/), [NOTCH1](https://onco.cc/targets/notch1/)
- pathways: [Notch signalling](https://onco.cc/pathways/notch/)
- journals: [Clinical Cancer Research](https://onco.cc/journals/clinical-cancer-research/)

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