1. Inhibition of dual-specificity tyrosine phosphorylation-regulated kinase 2 perturbs 26S proteasome-addicted neoplastic progression
- Author
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Jenna J Lee, Haydee L. Gutierrez, Sourav Banerjee, Junyu Xiao, Liang Ruqi, Sandra E. Wiley, Vasudha Tandon, Tiantian Wei, Jue Wang, Kimberly L. Cooper, Lukas Chavez, Edwin F. Juarez, Xiaoguang Lei, Caitlin Costello, Jack E. Dixon, Owen Chapman, Laureano de la Vega, Jill P. Mesirov, Robert L. Sah, and Joshua E. Mayfield
- Subjects
Triple Negative Breast Neoplasms ,Inbred C57BL ,Bortezomib ,chemistry.chemical_compound ,Mice ,Gene Knockout Techniques ,0302 clinical medicine ,Phosphorylation ,Multiple myeloma ,Triple-negative breast cancer ,Inbred BALB C ,Cancer ,Gene Editing ,0303 health sciences ,Mice, Inbred BALB C ,Multidisciplinary ,Tumor ,Kinase ,Biological Sciences ,Protein-Tyrosine Kinases ,Protein-Serine-Threonine Kinases ,3. Good health ,multiple myeloma ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,triple-negative breast cancer ,Female ,Development of treatments and therapeutic interventions ,Proteasome Inhibitors ,medicine.drug ,Proteasome Endopeptidase Complex ,kinase inhibitor ,Protein Serine-Threonine Kinases ,Cell Line ,03 medical and health sciences ,Rare Diseases ,In vivo ,Cell Line, Tumor ,Breast Cancer ,medicine ,Genetics ,Animals ,Humans ,030304 developmental biology ,Neoplastic Processes ,Pharmacology ,TYK2 Kinase ,business.industry ,proteasome inhibitor ,DYRK ,Human Genome ,Tyrosine phosphorylation ,medicine.disease ,Mice, Inbred C57BL ,Orphan Drug ,HEK293 Cells ,chemistry ,Proteasome ,Gene Expression Regulation ,Proteasome inhibitor ,Cancer research ,ATPases Associated with Diverse Cellular Activities ,business - Abstract
Significance Multiple myeloma (MM) and triple-negative breast cancer (TNBC) are dependent on 26S proteasome for malignancy. We have previously shown that the proteasome-regulating kinase DYRK2 is a viable target for both MM and TNBC. Here we identified a specific DYRK2 inhibitor, LDN192960, which alleviates both MM and TNBC progression via mechanisms including partial inhibition of proteasome activity. At this time we report a single drug target for 2 diverse cancers and highlight the importance of identifying proteasome regulators., 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.
- Published
- 2019