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c-kit Receptor Expression in Ewing’s Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions

Katia Scotlandi, Maria Cristina Manara, Rosaria Strammiello, Lorena Landuzzi, Stefania Benini, Stefania Perdichizzi, Massimo Serra, Alessia Astolfi, Giordano Nicoletti, Pier-Luigi Lollini, Franco Bertoni, Patrizia Nanni, Piero Picci

From the Laboratorio di Ricerca Oncologica and Servizio di Anatomia Patologica, Istituti Ortopedici Rizzoli; Sezione di Cancerologia, Università di Bologna, Bologna, Italy.

Address reprint requests to Katia Scotlandi, PhD, Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy; email: katia.scotlandi{at}ior.it.

Purpose: Autocrine/paracrine stimulation of c-kit has been recently observed in Ewing’s sarcoma (ES) cell lines. In this study, we tested the prognostic and therapeutic role of the receptor in this tumor.

Methods: One hundred one ES tumor biopsies were evaluated for the expression of c-kit by the avidin-biotin-peroxidase procedure. Effectiveness of STI-571 (Gleevec; Novartis, Basel, Switzerland), a selective inhibitor of specific tyrosine kinases, was analyzed with respect to in vitro growth and migration inhibition, as single agent or in combination with doxorubicin.

Results: Approximately 30% of patients expressed c-kit in their primary tumors. No significant association between the expression of the receptor and the clinical outcome was observed. In vitro growth of ES cell lines showing high levels of c-kit demonstrated limited inhibition by exposure to STI-571 (10 µmol/L is required to obtain 40% to 50% of growth inhibition). A decrease of stem-cell factor–mediated ES cell migration was also found. The drug acted additively with doxorubicin in inhibiting ES cell growth.

Conclusion: The negative prognostic findings and the limited in vitro therapeutic activity of STI-571 indicate that the putative aberrant signaling provided by c-kit overexpression may be dispensable for ES development and unlikely to constitute a critical therapeutic target. Accordingly, the dose of STI-571 required to give a significant ES growth inhibition is much higher than for those tumors in which mutations of c-kit constitute a relevant pathogenetic event. Nevertheless, in the subset of ES patients showing a high level of c-kit expression, the activity of the drug may be exploited in combination with standard therapy.

Supported by the Italian Association for Cancer Research, Italian Ministry of Health, and Italian Ministry for Education, University, and Research.

V.C. and R.S. are in receipt of Italian Foundation for Cancer Research Fellowships.

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