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      Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma

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          Abstract

          Publisher's Note: There is an [Related article:]Inside Blood Commentary on this article in this issue.

          Key Points

          • Apilimod has broad anticancer activity in vitro and in vivo across all subtypes of B-NHL.

          • Apilimod induces B-NHL cytotoxicity through a unique mechanism of action that involves the disruption of lysosomal function.

          Abstract

          We identified apilimod as an antiproliferative compound by high-throughput screening of clinical-stage drugs. Apilimod exhibits exquisite specificity for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) lipid kinase and has selective cytotoxic activity in B-cell non-Hodgkin lymphoma (B-NHL) compared with normal cells. Apilimod displays nanomolar activity in vitro, and in vivo studies demonstrate single-agent efficacy as well as synergy with approved B-NHL drugs. Using biochemical and knockdown approaches, and discovery of a kinase domain mutation conferring resistance, we demonstrate that apilimod-mediated cytotoxicity is driven by PIKfyve inhibition. Furthermore, a critical role for lysosome dysfunction as a major factor contributing to apilimod’s cytotoxicity is supported by a genome-wide CRISPR screen. In the screen, TFEB (master transcriptional regulator of lysosomal biogenesis) and endosomal/lysosomal genes CLCN7, OSTM1, and SNX10 were identified as important determinants of apilimod sensitivity. These findings thus suggest that disruption of lysosomal homeostasis with apilimod represents a novel approach to treat B-NHL.

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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          30 March 2017
          19 January 2017
          30 March 2017
          : 129
          : 13
          : 1768-1778
          Affiliations
          [1 ]LAM Therapeutics, Guilford, CT;
          [2 ]Program in Cellular Neuroscience, Neurodegeneration and Repair, Department of Cell Biology, Yale University School of Medicine, New Haven, CT;
          [3 ]Department of Cancer Pharmacology, Crown Bioscience Inc., Beijing, People’s Republic of China;
          [4 ]Howard Hughes Medical Institute, New Haven, CT; and
          [5 ]Department of Genetics, Yale University School of Medicine, New Haven, CT
          Author notes
          [*]

          S.G., S.L., and N.B. contributed equally to this work.

          Article
          PMC5766845 PMC5766845 5766845 2016/736892
          10.1182/blood-2016-09-736892
          5766845
          28104689
          28639562-e5eb-46bd-bac9-61749fe43c25
          © 2017 by The American Society of Hematology
          History
          : 01 September 2016
          : 12 January 2017
          Page count
          Pages: 11
          Categories
          39
          Lymphoid Neoplasia
          Custom metadata
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