B-cell non-Hodgkin lymphoma: Selective vulnerability to PIKFYVE inhibition

We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption...

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Bibliographic Details
Published in:Autophagy 2017-06, Vol.13 (6), p.1082-1083
Main Authors: Gayle, Sophia, Landrette, Sean, Beeharry, Neil, Conrad, Chris, Hernandez, Marylens, Beckett, Paul, Ferguson, Shawn M., Xu, Tian, Rothberg, Jonathan, Lichenstein, Henri
Format: Article
Language:English
Subjects:
apilimod
Autophagic Punctum
autophagy
B-Lymphocytes - drug effects
B-Lymphocytes - enzymology
B-Lymphocytes - pathology
CLCN7
Endosomes - metabolism
Humans
lymphoma
Lymphoma, Non-Hodgkin - drug therapy
Lymphoma, Non-Hodgkin - enzymology
Lymphoma, Non-Hodgkin - pathology
Lysosomes - metabolism
Models, Biological
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
PIKFYVE
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
TFEB
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Summary:We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity. Together these data highlight disruption of lysosome homeostasis through PIKFYVE inhibition as a novel anticancer mechanism in B-NHL and potentially other cancers.
ISSN:1554-8627
1554-8635
DOI:10.1080/15548627.2017.1304871