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[Cancer Research 62, 1077-1082, February 15, 2002]
© 2002 American Association for Cancer Research

Experimental Therapeutics

The Kinase Inhibitor PP1 Blocks Tumorigenesis Induced by RET Oncogenes1

Francesca Carlomagno2, Donata Vitagliano, Teresa Guida, Maria Napolitano, Giancarlo Vecchio, Alfredo Fusco, Aviv Gazit, Alexander Levitzki and Massimo Santoro

Centro di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Facoltà di Medicina e Chirurgia, Università di Napoli "Federico II," 80131 Naples, Italy [F. C., D. V., T. G., G. V., A. F., M. S.); Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904 Israel [A. L., A. G.]; and Fondazione Senatore Pascale, 80131 Naples, Italy [M. N.]

Oncogenic activation of the RET receptor tyrosine kinase is common in different human cancers. We found that the pyrazolo-pyrimidine PP1 inhibited RET-derived oncoproteins with a half maximal inhibitor concentration of 80 nM. Furthermore, RET/PTC3-transformed cells treated with 5 µM of PP1 lost proliferative autonomy and showed morphological reversion. PP1 prevented the growth of two human papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1 rearrangements and blocked anchorage-independent growth and tumorigenicity in nude mice of NIH3T3 fibroblasts expressing the RET/PTC3 oncogene. These findings suggest targeting RET oncogenes with PP1 or related compounds as a novel treatment strategy for RET-associated neoplasms.




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