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 languageEnglish
Pages (from-to)24881-24891
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number49
Early online date21 Nov 2019
DOIs
Publication statusPublished - 3 Dec 2019

Keywords

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

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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