Constitutively active receptor tyrosine kinases as oncogenes in preclinical models for cancer therapeutics.
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.
Kellar
Kristen A
KA
Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.
Lorenzi
Matthew V
MV
Ho
Ching Ping
CP
You
Dan
D
Wen
Mei-Li
ML
Ryseck
Rolf P
RP
Oppenheimer
Simone
S
Fink
Brian E
BE
Vite
Gregory D
GD
Rowley
Bruce R
BR
Yu
Chiang
C
Bol
David K
DK
Lee
Francis Y
FY
Wong
Tai W
TW
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
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