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.

Sourav Banerjee ¹, Tiantian Wei ² ³, Jue Wang ⁴, Jenna J Lee ⁵, Haydee L Gutierrez ⁶, Owen Chapman ⁷, Sandra E Wiley ¹, Joshua E Mayfield ¹, Vasudha Tandon ¹, Edwin F Juarez ⁷, Lukas Chavez ⁷ ⁸, Ruqi Liang ² ³, Robert L Sah ⁵, Caitlin Costello ⁸ ⁹, Jill P Mesirov ⁷ ⁸, Laureano de la Vega ¹⁰, Kimberly L Cooper ⁶, 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; [email protected] [email protected] [email protected].
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; [email protected] [email protected] [email protected].
15 Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China; [email protected] [email protected] [email protected].
16 Department of Chemical Biology, Synthetic and Functional Biomolecules Center, Peking University, 100871 Beijing, China.

PMID: 31754034 DOI: 10.1073/pnas.1912033116

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.

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