論文 - 詳細
| RRC ID | 45223 |
|---|---|
| 著者 | Stoeck A, Lejnine S, Truong A, Pan L, Wang H, Zang C, Yuan J, Ware C, MacLean J, Garrett-Engele PW, Kluk M, Laskey J, Haines BB, Moskaluk C, Zawel L, Fawell S, Gilliland G, Zhang T, Kremer BE, Knoechel B, Bernstein BE, Pear WS, Liu XS, Aster JC, Sathyanarayanan S. |
| タイトル | Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. |
| ジャーナル | Cancer Discov |
| Abstract |
UNLABELLED: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. |
| 巻・号 | 4(10) |
| ページ | 1154-67 |
| 公開日 | 2014-10-1 |
| DOI | 10.1158/2159-8290.CD-13-0830 |
| PII | 2159-8290.CD-13-0830 |
| PMID | 25104330 |
| PMC | PMC4184927 |
| MeSH | Amyloid Precursor Protein Secretases / antagonists & inhibitors* Animals Antineoplastic Agents / administration & dosage Antineoplastic Agents / pharmacology* Apoptosis / drug effects Apoptosis / genetics Biomarkers Carcinoma, Adenoid Cystic / drug therapy Carcinoma, Adenoid Cystic / genetics* Carcinoma, Adenoid Cystic / metabolism Cell Line, Tumor Cellular Senescence / drug effects Cyclic S-Oxides / pharmacology Disease Models, Animal Drug Resistance, Neoplasm / genetics Exome Female Gene Expression Regulation, Neoplastic Gene Rearrangement Genes, myc High-Throughput Nucleotide Sequencing Humans Models, Molecular Mutation Prognosis Protease Inhibitors / administration & dosage Protease Inhibitors / pharmacology* Protein Conformation Protein Interaction Domains and Motifs Receptors, Notch / antagonists & inhibitors Receptors, Notch / chemistry Receptors, Notch / genetics Receptors, Notch / metabolism Signal Transduction / drug effects Thiadiazoles / pharmacology Treatment Outcome Triple Negative Breast Neoplasms / drug therapy Triple Negative Breast Neoplasms / genetics* Triple Negative Breast Neoplasms / metabolism Xenograft Model Antitumor Assays |
| IF | 29.497 |
| 引用数 | 64 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | OCUB-M(RCB0881) |