Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Sourav Banerjee; Tiantian Wei; Jue Wang; Jenna J. Lee; Haydee L. Gutierrez; Owen Chapman; Sandra E. Wiley; Joshua E. Mayfield; Vasudha Tandon; Edwin F. Juarez; Lukas Chavez; Ruqi Liang; Robert L. Sah; Caitlin Costello; Jill P. Mesirov; Laureano de la Vega; Kimberly L. Cooper; Jack E. Dixon; Junyu Xiao; Xiaoguang Lei

doi:10.1073/pnas.1912033116

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Sourav Banerjee, Tiantian Wei, Jue Wang, Jenna J. Lee, Haydee L. Gutierrez, Owen Chapman, Sandra E. Wiley, Joshua E. Mayfield, Vasudha Tandon, Edwin F. Juarez, Lukas Chavez, Ruqi Liang, Robert L. Sah, Caitlin Costello, Jill P. Mesirov, Laureano de la Vega, Kimberly L. Cooper, Jack E. Dixon (Lead / Corresponding author), Junyu Xiao, Xiaoguang Lei

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Abstract

Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

Original language	English
Pages (from-to)	24881-24891
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	49
Early online date	21 Nov 2019
DOIs	https://doi.org/10.1073/pnas.1912033116
Publication status	Published - 3 Dec 2019

Keywords

DYRK
Inhibitor
Kinase
Multiple myeloma
Proteasome inhibitor
Triple-negative breast cancer

ASJC Scopus subject areas

General

UN SDGs

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

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10.1073/pnas.1912033116Licence: CC BY-NC-ND

Final Published VersionFinal published version, 2.04 MBLicence: CC BY-NC-ND

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Banerjee, S., Wei, T., Wang, J., Lee, J. J., Gutierrez, H. L., Chapman, O., Wiley, S. E., Mayfield, J. E., Tandon, V., Juarez, E. F., Chavez, L., Liang, R., Sah, R. L., Costello, C., Mesirov, J. P., de la Vega, L., Cooper, K. L., Dixon, J. E., Xiao, J., & Lei, X. (2019). Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression. Proceedings of the National Academy of Sciences of the United States of America, 116(49), 24881-24891. https://doi.org/10.1073/pnas.1912033116

@article{24c525d7fba0435d9e6760ab8ce61b4b,

title = "Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression",

abstract = "Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.",

keywords = "DYRK, Inhibitor, Kinase, Multiple myeloma, Proteasome inhibitor, Triple-negative breast cancer",

author = "Sourav Banerjee and Tiantian Wei and Jue Wang and Lee, {Jenna J.} and Gutierrez, {Haydee L.} and Owen Chapman and Wiley, {Sandra E.} and Mayfield, {Joshua E.} and Vasudha Tandon and Juarez, {Edwin F.} and Lukas Chavez and Ruqi Liang and Sah, {Robert L.} and Caitlin Costello and Mesirov, {Jill P.} and {de la Vega}, Laureano and Cooper, {Kimberly L.} and Dixon, {Jack E.} and Junyu Xiao and Xiaoguang Lei",

note = "Copyright {\textcopyright} 2019 the Author(s). Published by PNAS.",

year = "2019",

month = dec,

day = "3",

doi = "10.1073/pnas.1912033116",

language = "English",

volume = "116",

pages = "24881--24891",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Banerjee, S, Wei, T, Wang, J, Lee, JJ, Gutierrez, HL, Chapman, O, Wiley, SE, Mayfield, JE, Tandon, V, Juarez, EF, Chavez, L, Liang, R, Sah, RL, Costello, C, Mesirov, JP, de la Vega, L, Cooper, KL, Dixon, JE, Xiao, J & Lei, X 2019, 'Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 49, pp. 24881-24891. https://doi.org/10.1073/pnas.1912033116

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression. / Banerjee, Sourav; Wei, Tiantian; Wang, Jue et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 49, 03.12.2019, p. 24881-24891.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

AU - Banerjee, Sourav

AU - Wei, Tiantian

AU - Wang, Jue

AU - Lee, Jenna J.

AU - Gutierrez, Haydee L.

AU - Chapman, Owen

AU - Wiley, Sandra E.

AU - Mayfield, Joshua E.

AU - Tandon, Vasudha

AU - Juarez, Edwin F.

AU - Chavez, Lukas

AU - Liang, Ruqi

AU - Sah, Robert L.

AU - Costello, Caitlin

AU - Mesirov, Jill P.

AU - de la Vega, Laureano

AU - Cooper, Kimberly L.

AU - Dixon, Jack E.

AU - Xiao, Junyu

AU - Lei, Xiaoguang

PY - 2019/12/3

Y1 - 2019/12/3

N2 - Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

AB - Dependence on the 26S proteasome is an Achilles' heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

KW - DYRK

KW - Inhibitor

KW - Kinase

KW - Multiple myeloma

KW - Proteasome inhibitor

KW - Triple-negative breast cancer

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U2 - 10.1073/pnas.1912033116

DO - 10.1073/pnas.1912033116

M3 - Article

C2 - 31754034

SN - 0027-8424

VL - 116

SP - 24881

EP - 24891

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 49

ER -

Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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de la Vega, Laureano

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Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Other files and links

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de la Vega, Laureano

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