title: Cabozantinib (XL184) Inhibits Growth and Invasion of Preclinical TNBC Models.
abstract: OBJECTIVE
  Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that is associated with poor clinical outcome. There is a vital need for effective targeted therapeutics for TNBC patients, yet treatment strategies are challenged by the significant intertumoral heterogeneity within the TNBC subtype and its surrounding microenvironment. Receptor tyrosine kinases (RTK) are highly expressed in several TNBC subtypes and are promising therapeutic targets. In this study, we targeted the MET receptor, which is highly expressed across several TNBC subtypes.
  
  
  METHODS
  Using the small-molecule inhibitor cabozantinib (XL184), we examined the efficacy of MET inhibition in preclinical models that recapitulate human TNBC and its microenvironment. To analyze the dynamic interactions between TNBC cells and fibroblasts over time, we utilized a 3D model referred to as MAME (Mammary Architecture and Microenvironment Engineering) with quantitative image analysis. To investigate cabozantinib inhibition in vivo, we used a novel xenograft model that expresses human HGF and supports paracrine MET signaling.
  
  
  RESULTS
  XL184 treatment of MAME cultures of MDA-MB-231 and HCC70 cells (± HGF-expressing fibroblasts) was cytotoxic and significantly reduced multicellular invasive outgrowths, even in cultures with HGF-expressing fibroblasts. Treatment with XL184 had no significant effects on MET(neg) breast cancer cell growth. In vivo assays demonstrated that cabozantinib treatment significantly inhibited TNBC growth and metastasis.
  
  
  CONCLUSIONS
  Using preclinical TNBC models that recapitulate the breast tumor microenvironment, we demonstrate that cabozantinib inhibition is an effective therapeutic strategy in several TNBC subtypes.
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Sameni
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tovar
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Curt J
authors.initials: CJ
authors.lastname: Essenburg
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Anita
authors.initials: A
authors.lastname: Chalasani
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Linklater
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Andrew
authors.initials: A
authors.lastname: Borgman
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: David M
authors.initials: DM
authors.lastname: Cherba
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Arulselvi
authors.initials: A
authors.lastname: Anbalagan
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan. carrie.graveel@vai.org.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Graveel
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met