Inhibition of USP10 induces degradation of oncogenic FLT3

An inhibitor of the deubiquitinase (DUB) USP10 regulates the degradation of oncogenic FLT3, thus defining USP10 as a DUB for FLT3 and providing a therapeutic approach for human acute myeloid leukemia in which FLT3 activation is dysregulated. Oncogenic forms of the kinase FLT3 are important therapeut...

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Published in:	Nature chemical biology Vol. 13; no. 12; pp. 1207 - 1215
Main Authors:	Weisberg, Ellen L, Schauer, Nathan J, Yang, Jing, Lamberto, Ilaria, Doherty, Laura, Bhatt, Shruti, Nonami, Atsushi, Meng, Chengcheng, Letai, Anthony, Wright, Renee, Tiv, Hong, Gokhale, Prafulla C, Ritorto, Maria Stella, De Cesare, Virginia, Trost, Matthias, Christodoulou, Alexandra, Christie, Amanda, Weinstock, David M, Adamia, Sophia, Stone, Richard, Chauhan, Dharminder, Anderson, Kenneth C, Seo, Hyuk-Soo, Dhe-Paganon, Sirano, Sattler, Martin, Gray, Nathanael S, Griffin, James D, Buhrlage, Sara J
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.12.2017 Nature Publishing Group
Subjects:	13 13/1 13/106 13/109 13/31 13/95 49/98 59/5 631/67/1059 631/92/468 631/92/555 82/80 82/83 Acute myeloid leukemia Animal models Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Biochemical Engineering Biochemistry Bioorganic Chemistry Cell Biology Cell Proliferation - drug effects Cell Survival - drug effects Chemistry Chemistry/Food Science Degradation Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Female fms-Like Tyrosine Kinase 3 - genetics fms-Like Tyrosine Kinase 3 - metabolism Humans Inhibitors Kinases Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Mice Mice, Inbred NOD Molecular Structure Mutation Myeloid leukemia Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Pharmacology Proteasomes Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Rodents Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship Thiophenes - chemistry Thiophenes - pharmacology Tumor Cells, Cultured Ubiquitin Ubiquitin - metabolism Ubiquitin Thiolesterase - antagonists & inhibitors Ubiquitin Thiolesterase - genetics Ubiquitin Thiolesterase - metabolism
ISSN:	1552-4450, 1552-4469, 1552-4469
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Summary:	An inhibitor of the deubiquitinase (DUB) USP10 regulates the degradation of oncogenic FLT3, thus defining USP10 as a DUB for FLT3 and providing a therapeutic approach for human acute myeloid leukemia in which FLT3 activation is dysregulated. Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Author Contributions E.L.W., S.J.B., N.S.G, and J.D.G. initiated the project and E.L.W. and S.J.B oversaw all aspects of the project. E.L.W., N.J.S., J.Y., and I.L. performed biochemical, proliferation, signaling, knockdown, overexpression, immunoprecipitation, and signaling studies. S.B. and A.T. designed and performed mitochondrial priming experiments. A.C., A.C. and D.M.W. designed and performed primagraft studies. H.T. and P.C.G. designed and performed in vivo bioluminescence studies. M.S.R, V.D.C., and M.T. designed and performed MALDI-TOF DUB assays. S. A. performed flow cytometry experiments. A. N. performed gene knockdown experiments. S.D. and H-S.S. are responsible for generation of USP10 enzyme used in biochemical assays. L.D., C.M., and R.W. performed immunoblotting experiments. R.S. provided AML patient samples. M.S, D.C., K.C.A., offered valuable scientific feedback and helped with conception of research reported in paper. E.L.W. and S.J.B. wrote the manuscript with input from all authors.
ISSN:	1552-4450 1552-4469 1552-4469
DOI:	10.1038/nchembio.2486