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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.
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.
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.
Shares Gamma-secretase (PSEN1), NOTCH1, Notch signalling, Triple-negative breast cancer (TNBC).
Shares Clinical Cancer Research, Triple-negative breast cancer (TNBC).
Shares Clinical Cancer Research, Triple-negative breast cancer (TNBC).
Shares Gamma-secretase (PSEN1), Notch signalling.
Shares Clinical Cancer Research, Triple-negative breast cancer (TNBC).
Shares Clinical Cancer Research, Triple-negative breast cancer (TNBC).
Shares Clinical Cancer Research, Triple-negative breast cancer (TNBC).
Shares Notch signalling, Triple-negative breast cancer (TNBC).