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 Stone; Dharminder Chauhan; Kenneth C. Anderson; Hyuk-Soo Seo; Sirano Dhe-Paganon; Martin Sattler; Nathanael S. Gray; James D. Griffin; Sara J. Buhrlage

doi:10.1038/nchembio.2486

Inhibition of USP10 induces degradation of oncogenic FLT3

Ellen L. Weisberg (Lead / Corresponding author), 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 (Lead / Corresponding author)

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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 language	English
Pages (from-to)	1207-1215
Number of pages	9
Journal	Nature Chemical Biology
Volume	13
Early online date	2 Oct 2017
DOIs	https://doi.org/10.1038/nchembio.2486
Publication status	Published - 2 Oct 2017

Keywords

Cancer therapy
Proteases
Target identification

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Weisberg, E. L., Schauer, N. J., Yang, J., Lamberto, I., Doherty, L., Bhatt, S., Nonami, A., Meng, C., Letai, A., Wright, R., Tiv, H., Gokhale, P. C., Ritorto, M. S., De Cesare, V., Trost, M., Christodoulou, A., Christie, A., Weinstock, D. M., Adamia, S., ... Buhrlage, S. J. (2017). Inhibition of USP10 induces degradation of oncogenic FLT3. Nature Chemical Biology, 13, 1207-1215. https://doi.org/10.1038/nchembio.2486

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title = "Inhibition of USP10 induces degradation of oncogenic FLT3",

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.",

keywords = "Cancer therapy, Proteases, Target identification",

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

note = "Work was funded by the Dana-Farber Cancer Institute Accelerator Fund (S.J.B. and E.L.W.), the Leukemia and Lymphoma Society (S.J.B. and E.L.W.), the Chleck Family Foundation (N.J.S.), the National Science Fellowship Graduate Research Fellowship Program (L.D.) and the and Claudia Adams Barr Award (S.J.B. and E.L.W.).",

year = "2017",

month = oct,

day = "2",

doi = "10.1038/nchembio.2486",

language = "English",

volume = "13",

pages = "1207--1215",

journal = "Nature Chemical Biology",

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Weisberg, EL, Schauer, NJ, Yang, J, Lamberto, I, Doherty, L, Bhatt, S, Nonami, A, Meng, C, Letai, A, Wright, R, Tiv, H, Gokhale, PC, Ritorto, MS, De Cesare, V, Trost, M, Christodoulou, A, Christie, A, Weinstock, DM, Adamia, S, Stone, R, Chauhan, D, Anderson, KC, Seo, H-S, Dhe-Paganon, S, Sattler, M, Gray, NS, Griffin, JD & Buhrlage, SJ 2017, 'Inhibition of USP10 induces degradation of oncogenic FLT3', Nature Chemical Biology, vol. 13, pp. 1207-1215. https://doi.org/10.1038/nchembio.2486

TY - JOUR

T1 - Inhibition of USP10 induces degradation of oncogenic FLT3

AU - Weisberg, Ellen L.

AU - Schauer, Nathan J.

AU - Yang, Jing

AU - Lamberto, Ilaria

AU - Doherty, Laura

AU - Bhatt, Shruti

AU - Nonami, Atsushi

AU - Meng, Chengcheng

AU - Letai, Anthony

AU - Wright, Renee

AU - Tiv, Hong

AU - Gokhale, Prafulla C.

AU - Ritorto, Maria Stella

AU - De Cesare, Virginia

AU - Trost, Matthias

AU - Christodoulou, Alexandra

AU - Christie, Amanda

AU - Weinstock, David M.

AU - Adamia, Sophia

AU - Stone, Richard

AU - Chauhan, Dharminder

AU - Anderson, Kenneth C.

AU - Seo, Hyuk-Soo

AU - Dhe-Paganon, Sirano

AU - Sattler, Martin

AU - Gray, Nathanael S.

AU - Griffin, James D.

AU - Buhrlage, Sara J.

N1 - Work was funded by the Dana-Farber Cancer Institute Accelerator Fund (S.J.B. and E.L.W.), the Leukemia and Lymphoma Society (S.J.B. and E.L.W.), the Chleck Family Foundation (N.J.S.), the National Science Fellowship Graduate Research Fellowship Program (L.D.) and the and Claudia Adams Barr Award (S.J.B. and E.L.W.).

PY - 2017/10/2

Y1 - 2017/10/2

N2 - 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.

AB - 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.

KW - Cancer therapy

KW - Proteases

KW - Target identification

U2 - 10.1038/nchembio.2486

DO - 10.1038/nchembio.2486

M3 - Article

C2 - 28967922

SN - 1552-4450

VL - 13

SP - 1207

EP - 1215

JO - Nature Chemical Biology

JF - Nature Chemical Biology

ER -

Inhibition of USP10 induces degradation of oncogenic FLT3

Abstract

Keywords

UN SDGs

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