Title |
Identification of a nucleoside analog active against adenosine kinase–expressing plasma cell malignancies
|
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Published in |
Journal of Clinical Investigation, May 2017
|
DOI | 10.1172/jci83936 |
Pubmed ID | |
Authors |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 5 | 45% |
United Kingdom | 1 | 9% |
Bosnia and Herzegovina | 1 | 9% |
France | 1 | 9% |
Unknown | 3 | 27% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 6 | 55% |
Scientists | 5 | 45% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 25 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 3 | 12% |
Other | 3 | 12% |
Student > Bachelor | 2 | 8% |
Student > Doctoral Student | 2 | 8% |
Student > Ph. D. Student | 2 | 8% |
Other | 5 | 20% |
Unknown | 8 | 32% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 28% |
Medicine and Dentistry | 4 | 16% |
Immunology and Microbiology | 1 | 4% |
Nursing and Health Professions | 1 | 4% |
Social Sciences | 1 | 4% |
Other | 1 | 4% |
Unknown | 10 | 40% |