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Updated: Aug 7, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
10:49

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Published on: September 18, 2013

Constitutively active receptor tyrosine kinases as oncogenes in preclinical models for cancer therapeutics

Kristen A Kellar1, Matthew V Lorenzi, Ching Ping Ho

  • 1Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA.

Molecular Cancer Therapeutics
|July 5, 2006
PubMed

Insights

Researchers developed novel chimeric receptors by fusing CD8 with receptor tyrosine kinases (RTK). These models, including CD8HER2 and CD8Met, effectively create tumors in mice, offering new ways to study RTK signaling and test kinase inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biotechnology

Background:

  • Receptor tyrosine kinases (RTK) are crucial in epithelial tumor development.
  • Targeted therapies for RTKs are of significant therapeutic interest.
  • Development of specific experimental models for RTKs is essential.

Purpose of the Study:

  • To create and characterize novel chimeric receptor models for studying RTK signaling.
  • To evaluate the potential of these models for cancer research and drug development.
  • To investigate the in vivo effects of specific RTK fusions.

Main Methods:

  • Constructing chimeric receptors by fusing CD8 extracellular domains with RTK cytoplasmic domains.
  • Utilizing fibroblast and epithelial cell transformation assays.
  • Generating transgenic mouse models expressing CD8HER2 and CD8Met fusion proteins.
  • Deriving allograft tumors and cell lines from these transgenic models.

Main Results:

  • CD8HER2 fusion proteins induced cell transformation and formed disulfide-mediated homodimers.
  • CD8RTK fusion proteins transformed rat kidney epithelial cells, reflecting native receptor signaling.
  • Transgenic mice expressing CD8HER2 and CD8Met developed salivary and mammary gland tumors.
  • Derived tumors and cell lines were sensitive to small molecule kinase inhibitors.

Conclusions:

  • Chimeric receptor models, such as CD8HER2 and CD8Met, are effective tools for studying RTK signaling pathways.
  • These models provide valuable platforms for characterizing RTK function and evaluating targeted therapies.
  • The developed transgenic tumors and cell lines offer a promising avenue for preclinical drug discovery against RTK-driven cancers.

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