Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99

Haydar Çelik, Marika Sciandra, Bess Flashner, Elif Gelmez, Neslihan Kayraklıoğlu, David V Allegakoen, Jeff R Petro, Erin J Conn, Sarah Hour, Jenny Han, Lalehan Oktay, Purushottam B Tiwari, Mutlu Hayran, Brent T Harris, Maria Cristina Manara, Jeffrey A Toretsky, Katia Scotlandi, Aykut Üren

Research output: Contribution to journalArticle

Abstract

Ewing sarcoma (ES) is an aggressive bone and soft tissue malignancy that predominantly affects children and adolescents. CD99 is a cell surface protein that is highly expressed on ES cells and is required to maintain their malignancy. We screened small molecule libraries for binding to extracellular domain of recombinant CD99 and subsequent inhibition of ES cell growth. We identified two structurally similar FDA-approved compounds, clofarabine and cladribine that selectively inhibited the growth of ES cells in a panel of 14 ES vs. 28 non-ES cell lines. Both drugs inhibited CD99 dimerization and its interaction with downstream signaling components. A membrane-impermeable analog of clofarabine showed similar cytotoxicity in culture, suggesting that it can function through inhibiting CD99 independent of DNA metabolism. Both drugs drastically inhibited anchorage-independent growth of ES cells, but clofarabine was more effective in inhibiting growth of three different ES xenografts. Our findings provide a novel molecular mechanism for clofarabine that involves direct binding to a cell surface receptor CD99 and inhibiting its biological activities.

Original languageEnglish
Pages (from-to)2181-2196
Number of pages16
JournalOncogene
Volume37
Issue number16
DOIs
Publication statusPublished - Apr 2018

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    Çelik, H., Sciandra, M., Flashner, B., Gelmez, E., Kayraklıoğlu, N., Allegakoen, D. V., Petro, J. R., Conn, E. J., Hour, S., Han, J., Oktay, L., Tiwari, P. B., Hayran, M., Harris, B. T., Manara, M. C., Toretsky, J. A., Scotlandi, K., & Üren, A. (2018). Clofarabine inhibits Ewing sarcoma growth through a novel molecular mechanism involving direct binding to CD99. Oncogene, 37(16), 2181-2196. https://doi.org/10.1038/s41388-017-0080-4