Department of Pharmacology, University of California San Diego, La Jolla, CA 92093.
The State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, 100871 Beijing, China.
Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24881-24891. doi: 10.1073/pnas.1912033116. Epub 2019 Nov 21.
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.
依赖 26S 蛋白酶体是三阴性乳腺癌（TNBC）和多发性骨髓瘤（MM）的致命弱点。治疗性蛋白酶体抑制剂硼替佐米成功靶向 MM，但常常导致耐药性疾病复发，并在乳腺癌中失败。在这里，我们表明，26S 蛋白酶体调节激酶 DYRK2 是 MM 和 TNBC 的治疗靶点。基因组编辑或小分子介导的 DYRK2 抑制显著降低 26S 蛋白酶体活性，绕过硼替佐米耐药性，并显著延迟 MM 和 TNBC 体内肿瘤生长，从而促进生存。我们进一步表征了强效和选择性 DYRK2 抑制剂 LDN192960 减轻体内肿瘤负担的能力。该药物与 DYRK2 的活性位点结合，并部分抑制蛋白酶体的所有 3 个核心肽酶活性。我们的结果表明，靶向 26S 蛋白酶体调节剂将为 MM 和 TNBC 的治疗策略铺平道路。
