© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 14, 1088-1089,
July 16, 2003
© 2003 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Potential Use of Imatinib in Ewing’s Sarcoma: Evidence for In Vitro and In Vivo Activity
Affiliation of authors: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Correspondence to: Melinda Merchant, M.D., Ph.D., National Cancer Institute, National Institutes of Health, 10 Center Dr. MSC 1298, Bldg. 10/13N240, Bethesda, MD 20892 (e-mail: merchanm{at}mail.nih.gov).
We were quite interested in the findings of Tamborini et al. regarding evidence for KIT activation in a majority of Ewing’s sarcoma tumor specimens. This finding extends those from our laboratory (1) and others (2) that have posited a KIT/stem cell factor (SCF) growth loop within Ewing’s sarcoma cell lines. Although both KIT and SCF are expressed in most Ewing’s sarcoma cell lines, exogenous SCF was required to detect phosphorylation of KIT in vitro (1,2). The baseline phosphorylation of KIT in tumor specimens as shown by Tamborini et al. suggests that the in vivo environment enhances activation of KIT in Ewing’s sarcomas above that demonstrated in vitro. Thus, the KIT/SCF growth loop may be autocrine and/or paracrine, involving stroma or other host cells within the tumor. Of note, endothelial cells are known to express KIT (3) and, thus, may play a role in the basal activation of KIT as observed in the tumor specimens. These results have several ramifications, including the possibility that the in vivo target of imatinib is not just the tumor cell itself but also includes the vasculature.
Although we agree that potential efficacy of imatinib should not be limited to gain-of-function mutations, it is not clear that the mechanism of action in Ewing’s sarcomas is due simply to KIT inhibition. Neither our work nor the present findings confirm that the antitumor effect of imatinib in Ewing’s sarcoma is due to inhibition of KIT. As we reported (1), the in vitro cytotoxicity occurs at a 10-fold higher concentration of imatinib than is required to inhibit KIT phosphorylation in the same Ewing’s sarcoma cells. At the very least, this difference suggests that there is another mechanism by which imatinib exerts its cytotoxicity in vitro. Further studies would be required to determine whether imatinib’s antitumor effect is mediated by an alternative mechanism in vivo. The phosphorylation status of KIT after imatinib administration in animal studies or in the ongoing phase II trials would be helpful in determining whether KIT inhibition plays a greater role in vivo.
REFERENCES
1 Merchant MS, Woo CW, Mackall CL, Thiele CJ. Potential use of imatinib in Ewing’s Sarcoma: evidence for in vitro and in vivo activity. J Natl Cancer Inst 2002;94:1673–9.
2 Ricotti E, Fagioli F, Garelli E, Linari C, Crescenzio N, Horenstein AL, et al. c-kit is expressed in soft tissue sarcoma of neuroectodermic origin and its ligand prevents apoptosis of neoplastic cells. Blood 1998;91:2397–405.
3 Miyamoto T, Sasaguri Y, Sugama K, Azakami S, Morimatsu M. Expression of the c-kit mRNA in human aortic endothelial cells. Biochem Mol Biol Int 1994;34:513–20.[Medline]
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