Identification of a Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies

Utthara Nayar, Weill Cornell Medical College
Jouliana Sadek, Weill Cornell Medical College
Jonathan Reichel, Weill Cornell Medical College
Denise Hernandez-Hopkins, Weill Cornell Medical College
Gunkut Akar, Weill Cornell Medical College
Peter J. Barelli, Weill Cornell Medical College
Michelle A. Sahai, Weill Cornell Medical College
Hufeng Zhou, Brigham and Women’s Hospital
Jennifer Totonchy, Chapman University
David Jayabalan, Weill Cornell Medical College
Ruben Niesvizky, Weill Cornell Medical College
Ilaria Guasparri, Weill Cornell Medical College
Duane Hassane, Weill Cornell Medical College
Yifang Liu, Weill Cornell Medical College
Shizuko Sei, National Cancer Institute at Frederick
Robert H. Shoemaker, National Cancer Institute at Frederick
J. David Warren, Weill Cornell Medical College
Olivier Elemento, Weill Cornell Medical College
Kenneth M. Kaye, Brigham and Women's Hospital
Ethel Cesarman, Weill Cornell Medical College

This article was originally published in Journal of Clinical Investigation, volume 127, issue 6, in 2017. DOI: 10.1172/JCI83936

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.