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Rearrangements that lock the NOTCH1 or NOTCH2 receptor on were found in 6 of 66 triple-negative breast cancers and no other solid tumour, and only the NOTCH1-rearranged models responded to a gamma-secretase inhibitor.
Next-generation sequencing of a large collection of solid tumours identified NOTCH1 and NOTCH2 rearrangements leading to constitutive activation confined to TNBC (6 of 66). TNBC cell lines with NOTCH1 rearrangements and high activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor MRK-003 alone and with paclitaxel in vitro and in vivo; NOTCH2-rearranged lines were resistant. N1-ICD staining in xenografts correlated with response and HES4 expression with patient outcome. Activating NOTCH1 point mutations were also found in adenoid cystic carcinoma.
NOTCH is a real but small driver segment in TNBC with a receptor-specific drug response, which is why NOTCH-directed trials require rearrangement or N1-ICD testing rather than treating all TNBC.
Shares Gamma-secretase (PSEN1), NOTCH1, Notch signalling, Triple-negative breast cancer (TNBC).
Shares Cancer Discovery, Triple-negative breast cancer (TNBC).
Shares Gamma-secretase (PSEN1), Notch signalling.
Shares Notch signalling, Triple-negative breast cancer (TNBC).
Shares Gamma-secretase (PSEN1), Notch signalling.