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

Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24881-24891. doi: 10.1073/pnas.1912033116. Epub 2019 Nov 21.

Authors

Sourav Banerjee¹, Tiantian Wei^{2

3}, Jue Wang⁴, Jenna J Lee⁵, Haydee L Gutierrez⁶, Owen Chapman⁷, Sandra E Wiley¹, Joshua E Mayfield¹, Vasudha Tandon¹, Edwin F Juarez⁷, Lukas Chavez^{7

8}, Ruqi Liang^{2

3}, Robert L Sah⁵, Caitlin Costello^{8

9}, Jill P Mesirov^{7

8}, Laureano de la Vega¹⁰, Kimberly L Cooper⁶, Jack E Dixon^{11

12

13}, Junyu Xiao^{14

3}, Xiaoguang Lei^{15

4

16}

Affiliations

¹ Department of Pharmacology, University of California San Diego, La Jolla, CA 92093.
² The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, 100871 Beijing, China.
³ Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China.
⁴ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, 100871 Beijing, China.
⁵ Department of Bioengineering, University of California San Diego, La Jolla, CA 92093.
⁶ Division of Biological Sciences, Section of Cellular and Developmental Biology, University of California San Diego, La Jolla, CA 92093.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA 92093.
⁸ Moores Cancer Center, University of California San Diego, La Jolla, CA 92093.
⁹ Division of Blood and Marrow Transplant, University of California San Diego, La Jolla, CA 92093.
¹⁰ Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, United Kingdom.
¹¹ Department of Pharmacology, University of California San Diego, La Jolla, CA 92093; jedixon@ucsd.edu junyuxiao@pku.edu.cn xglei@pku.edu.cn.
¹² Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093.
¹³ Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093.
¹⁴ The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, 100871 Beijing, China; jedixon@ucsd.edu junyuxiao@pku.edu.cn xglei@pku.edu.cn.
¹⁵ Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China; jedixon@ucsd.edu junyuxiao@pku.edu.cn xglei@pku.edu.cn.
¹⁶ Department of Chemical Biology, Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China.

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; kinase inhibitor; multiple myeloma; proteasome inhibitor; triple-negative breast cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATPases Associated with Diverse Cellular Activities / genetics
Animals
Bortezomib / pharmacology*
Cell Line, Tumor
Dyrk Kinases
Female
Gene Editing
Gene Expression Regulation
Gene Knockout Techniques
HEK293 Cells
Humans
Mice, Inbred BALB C
Mice, Inbred C57BL
Multiple Myeloma
Neoplastic Processes*
Phosphorylation
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / pharmacology
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism*
TYK2 Kinase / metabolism*
Triple Negative Breast Neoplasms / metabolism*
Triple Negative Breast Neoplasms / pathology

Substances

Proteasome Inhibitors
Bortezomib
Protein-Tyrosine Kinases
TYK2 Kinase
Protein Serine-Threonine Kinases
PSMB5 protein, human
PSMC4 protein, human
Proteasome Endopeptidase Complex
ATP dependent 26S protease
ATPases Associated with Diverse Cellular Activities

Associated data

PDB/6K0J

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding