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

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

N1 - Copyright © 2019 the Author(s). Published by PNAS.

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

UR - https://www.scopus.com/pages/publications/85076026951

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 -