Inhibition of USP10 induces degradation of oncogenic FLT3

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....

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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	United States Nature Publishing Group 01.12.2017
Subjects	Acute myeloid leukemia Animal models Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Proliferation - drug effects Cell Survival - drug effects 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
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Summary:	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:	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
DOI:	10.1038/nchembio.2486