title: Constitutively active receptor tyrosine kinases as oncogenes in preclinical models for cancer therapeutics.
abstract: Receptor tyrosine kinases (RTK) remain an area of therapeutic interest because of their role in epithelial tumors, and experimental models specific to these targets are highly desirable. Chimeric receptors were prepared by in-frame fusion of the CD8 extracellular sequence with the cytoplasmic sequences of RTKs. A CD8HER2 fusion protein was shown to form disulfide-mediated homodimers and to transform fibroblasts and epithelial cells. CD8RTK fusion proteins transform rat kidney epithelial cells and impart phenotypes that may reflect signaling specificity inherent in the native receptors. Transgenic expression of CD8HER2 and CD8Met in mice resulted in the formation of salivary and mammary gland tumors. The transgenic tumors allow the derivation of allograft tumors and cell lines that are sensitive to inhibition by small molecule kinase inhibitors. This approach provides excellent cell and tumor models for the characterization of signaling properties of diverse RTKs and for the evaluation of rationally designed antagonists targeting these kinases.
authors.affiliation: Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Kellar
authors.forename: Matthew V
authors.initials: MV
authors.lastname: Lorenzi
authors.forename: Ching Ping
authors.initials: CP
authors.lastname: Ho
authors.forename: Dan
authors.initials: D
authors.lastname: You
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Wen
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Ryseck
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fink
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rowley
authors.forename: Chiang
authors.initials: C
authors.lastname: Yu
authors.forename: David K
authors.initials: DK
authors.lastname: Bol
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016827:CD8 Antigens / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019281:Dimerization; D004195:Disease Models, Animal; D004220:Disulfides / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D010957:Plasmids; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D014162:Transfection
chemical_list: D016827:CD8 Antigens; D004220:Disulfides; D010446:Peptide Fragments; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C409469:CD8 antigen, alpha chain