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

TY - JOUR

T1 - Identification of a nucleoside analog active against adenosine kinase-expressing plasma cell malignancies

AU - Nayar, Utthara

AU - Sadek, Jouliana

AU - Reichel, Jonathan

AU - Hernandez-Hopkins, Denise

AU - Akar, Gunkut

AU - Barelli, Peter J

AU - Sahai, Michelle A

AU - Zhou, Hufeng

AU - Totonchy, Jennifer

AU - Jayabalan, David

AU - Niesvizky, Ruben

AU - Guasparri, Ilaria

AU - Hassane, Duane

AU - Liu, Yifang

AU - Sei, Shizuko

AU - Shoemaker, Robert H.

AU - Warren, J. David

AU - Elemento, Olivier

AU - Kaye, Kenneth M.

AU - Cesarman, Ethel

PY - 2017/5/15

Y1 - 2017/5/15

N2 - 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. 

AB - 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. 

KW - Journal Article

U2 - 10.1172/JCI83936

DO - 10.1172/JCI83936

M3 - Article

C2 - 28504647

SN - 0021-9738

JO - The Journal of clinical investigation

JF - The Journal of clinical investigation

ER -