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

TitleIdentification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies.
Publication TypeJournal Article
Year of Publication2017
AuthorsNayar U, Sadek J, Reichel J, Hernandez-Hopkins D, Akar G, Barelli PJ, Sahai MA, Zhou H, Totonchy J, Jayabalan D, Niesvizky R, Guasparri I, Hassane D, Liu Y, Sei S, Shoemaker RH, J Warren D, Elemento O, Kaye KM, Cesarman E
JournalJ Clin Invest
Volume127
Issue6
Pagination2066-2080
Date Published2017 Jun 01
ISSN1558-8238
KeywordsAdenosine Kinase, Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Humans, Inhibitory Concentration 50, Lymphoma, Primary Effusion, Male, Mice, Mice, Inbred NOD, Mice, SCID, Purine Nucleosides, Xenograft Model Antitumor Assays
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.

DOI10.1172/JCI83936
Alternate JournalJ. Clin. Invest.
PubMed ID28504647
PubMed Central IDPMC5451239
Grant ListT32 AI007621 / AI / NIAID NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
R01 CA154228 / CA / NCI NIH HHS / United States
R01 CA082036 / CA / NCI NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States