Inhibition of USP10 induces degradation of oncogenic FLT3

Ellen L. Weisberg, Nathan J. Schauer, Jing Yang, Ilaria Lamberto, Laura Doherty, Shruti Bhatt, Atsushi Nonami, Chengcheng Meng, Anthony Letai, Renee Wright, Hong Tiv, Prafulla C. Gokhale, Maria Stella Ritorto, Virginia De Cesare, Matthias Trost, Alexandra Christodoulou, Amanda Christie, David M. Weinstock, Sophia Adamia, Richard StoneDharminder Chauhan, Kenneth C. Anderson, Hyuk Soo Seo, Sirano Dhe-Paganon, Martin Sattler, Nathanael S. Gray, James D. Griffin, Sara J. Buhrlage

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1207-1215
Number of pages9
JournalNature Chemical Biology
Volume13
Issue number12
DOIs
Publication statusPublished - Dec 1 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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