title: Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts. ssathy@jouncetx.com jaster@rics.bwh.harvard.edu Alexander.Stoeck@merck.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stoeck
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Serguei
authors.initials: S
authors.lastname: Lejnine
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Andrew
authors.initials: A
authors.lastname: Truong
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Li
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Chongzhi
authors.initials: C
authors.lastname: Zang
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Chris
authors.initials: C
authors.lastname: Ware
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: MacLean
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Garrett-Engele
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Kluk
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Jason
authors.initials: J
authors.lastname: Laskey
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.affiliation: Department of Medicine and Digestive Health Research Center, University of Virginia, Charlottesville, Virginia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Moskaluk
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Leigh
authors.initials: L
authors.lastname: Zawel
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Gary
authors.initials: G
authors.lastname: Gilliland
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Kremer
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Birgit
authors.initials: B
authors.lastname: Knoechel
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
authors.affiliation: Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.affiliation: Merck Research Laboratory, Boston, Massachusetts. ssathy@jouncetx.com jaster@rics.bwh.harvard.edu Alexander.Stoeck@merck.com.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathyanarayanan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D016259:Genes, myc; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011379:Prognosis; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D003499:Cyclic S-Oxides; C523799:MRK 003; D011480:Protease Inhibitors; D051880:Receptors, Notch; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases
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