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Tumor Development by Transgenic Expression of a Constitutively Active Insulin-Like Growth Factor I Receptor

¹ Oncology Drug Discovery and ² Discovery Toxicology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey; ³ The Breast Center and ⁴ The Children's Nutrition and Research Center, Departments of Medicine, Pediatrics, and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas; and ⁵ Discovery Chemistry, Bristol-Myers Squibb Research Institute, Wallingford, Connecticut

Requests for reprints: Tai W. Wong, Pharm Research Institute Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08534. Phone: 609-252-4187; Fax: 609-252-6171; E-mail: tai.wong{at}bms.com.

The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.

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