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(American Journal of Pathology. 2002;161:781-786.)
© 2002 American Society for Investigative Pathology

Technical Advance

Functional Tyrosine Kinase Inhibitor Profiling

A Generally Applicable Method Points to a Novel Role of Platelet-Derived Growth Factor Receptor-ß in Tuberous Sclerosis

Jack L. Arbiser^*, Baskaran Govindarajan^*, Xianhe Bai^*, Hiroaki Onda, Andrius Kazlauskas, So Dug Lim, Mahul B. Amin and Lena Claesson-Welsh^¶

From the Departments of Dermatology^* and Pathology, Emory University School of Medicine, Atlanta, Georgia; the Schepens Eye Institute and the Department of Adult Oncology, Harvard Medical School, Boston, Massachusetts; and the Department of Genetics and Pathology,^¶ Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-ß (PDGFRß) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it. We describe a simple and rapid method to assess functional activity of tyrosine kinase signaling that is broadly applicable to tumor types. As proof of principle, we have applied it to cells that serve as models of the autosomal-dominant tumor syndrome tuberous sclerosis (TS). We found that TS model cells derived from tuberin heterozygous mice and from a human renal angiomyolipoma are highly sensitive to PDGFR antagonists and that these cells express PDGFRß. Given that PDGFRß signaling is inhibited by STI571, we found that SV7tert human angiomyolipoma cells are sensitive to STI571. Thus, we describe a novel but simple method of determining the functional tyrosine kinase profile of a neoplastic cell and our results suggest that STI571 might be useful in the treatment of neoplasms commonly seen in patients with TS.

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