Abstract
Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD-low tumors without NOTCH1 mutations were resistant.
Significance:
NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies.
©2014 American Association for Cancer Research.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Biomarkers
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Carcinoma, Adenoid Cystic / drug therapy
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Carcinoma, Adenoid Cystic / genetics*
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Carcinoma, Adenoid Cystic / metabolism
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Cell Line, Tumor
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Cellular Senescence / drug effects
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Cyclic S-Oxides / pharmacology
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics
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Exome
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Female
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Gene Expression Regulation, Neoplastic
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Gene Rearrangement
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Genes, myc
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High-Throughput Nucleotide Sequencing
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Humans
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Models, Molecular
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Mutation
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Prognosis
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / pharmacology*
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Protein Conformation
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Protein Interaction Domains and Motifs
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Receptors, Notch / antagonists & inhibitors
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Receptors, Notch / chemistry
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Signal Transduction / drug effects
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Thiadiazoles / pharmacology
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Treatment Outcome
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Triple Negative Breast Neoplasms / drug therapy
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Triple Negative Breast Neoplasms / genetics*
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Triple Negative Breast Neoplasms / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Biomarkers
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Cyclic S-Oxides
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MRK 003
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Protease Inhibitors
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Receptors, Notch
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Thiadiazoles
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Amyloid Precursor Protein Secretases