Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies

Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J Barelli, Michelle A Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman

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Abstract

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase-inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further, we observed that 6-ETI induces ATP depletion and cell death accompanied by S phase arrest and DNA damage only in ADK-expressing cells. Immunohistochemistry for ADK served as a biomarker approach to identify 6-ETI-sensitive tumors, which we documented for other lymphoid malignancies with plasmacytic features. Notably, multiple myeloma (MM) expresses high levels of ADK, and 6-ETI was toxic to MM cell lines and primary specimens and had a robust antitumor effect in a disseminated MM mouse model. Several nucleoside analogs are effective in treating leukemias and T cell lymphomas, and 6-ETI may fill this niche for the treatment of PEL, plasmablastic lymphoma, MM, and other ADK-expressing cancers.

© 2017, American Society for Clinical Investigation. This is the final published version of the article (version of record) uploaded in accordance with the publisher’s self- archiving policy. It first appeared online at https://www.jci.org/articles/view/83936. 

Original languageEnglish
JournalThe Journal of clinical investigation
Early online date15 May 2017
DOIs
Publication statusE-pub ahead of print - 15 May 2017

Keywords

  • Journal Article

Cite this

Nayar, U., Sadek, J., Reichel, J., Hernandez-Hopkins, D., Akar, G., Barelli, P. J., Sahai, M. A., Zhou, H., Totonchy, J., Jayabalan, D., Niesvizky, R., Guasparri, I., Hassane, D., Liu, Y., Sei, S., Shoemaker, R. H., Warren, J. D., Elemento, O., Kaye, K. M., & Cesarman, E. (2017). Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies. The Journal of clinical investigation. https://doi.org/10.1172/JCI83936