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Cancer Discov. 2014 Oct;4(10):1154-67. doi: 10.1158/2159-8290.CD-13-0830. Epub 2014 Aug 7.

Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.

Author information

1
Merck Research Laboratory, Boston, Massachusetts. ssathy@jouncetx.com jaster@rics.bwh.harvard.edu Alexander.Stoeck@merck.com.
2
Merck Research Laboratory, Boston, Massachusetts.
3
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Department of Medicine and Digestive Health Research Center, University of Virginia, Charlottesville, Virginia.
6
Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
7
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

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.

PMID:
25104330
PMCID:
PMC4184927
DOI:
10.1158/2159-8290.CD-13-0830
[Indexed for MEDLINE]
Free PMC Article

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