Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast cancer and Adenoid Cystic carcinoma

Alexander Stoeck, Serguei Lejnine, Andrew Truong, L. Pan, Hongfang Wang, Chongzhi Zang, Jing Yuan, Chris Ware, John Maclean, Philip W. Garrett-Engele, Michael Kluk, Jason Laskey, Brian B. Haines, Christopher Moskaluk, Leigh Zawel, Stephen Fawell, Gary Gilliland, Theresa Zhang, Brandon E. Kremer, Birgit KnoechelBradley E. Bernstein, Warren S. Pear, X. Shirley Liu, Jon C. Aster, Sriram Sathyanarayanan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 confi ned 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 identifi ed 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.

Original languageEnglish
Pages (from-to)1154-1167
Number of pages14
JournalCancer Discovery
Volume4
Issue number10
DOIs
StatePublished - 1 Oct 2014
Externally publishedYes

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