title: A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer.
abstract: Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1-targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: W M
authors.initials: WM
authors.lastname: Tai
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Ryan
authors.initials: R
authors.lastname: McWilliams
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Stacey
authors.initials: S
authors.lastname: Bagby
authors.affiliation: Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Blatchford
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Alicia
authors.initials: A
authors.lastname: Purkey
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Quackenbush
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Song
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: Department of Biostatistics & Informatics, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Dexiang
authors.initials: D
authors.lastname: Gao
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Chris
authors.initials: C
authors.lastname: Lieu
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Martine
authors.initials: M
authors.lastname: McManus
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA.
authors.forename: Xianxian
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ozeck
authors.affiliation: Pfizer Oncology Research Unit, Translational Research, Pfizer, La Jolla, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Olson
authors.affiliation: MD Anderson Cancer Center, Texas Medical Center, Houston, TX.
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Jiang
authors.affiliation: MD Anderson Cancer Center, Texas Medical Center, Houston, TX.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Stephen
authors.initials: S
authors.lastname: Keysar
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Gail
authors.initials: G
authors.lastname: Eckhardt
authors.affiliation: Division of Medical Oncology, University of Colorado Denver Anschutz Medical Campus and University of Colorado Cancer Center, Aurora, CO.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D011379:Prognosis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins
keywords: Notch1; biomarker; colorectal cancer