Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+breast cancer

被引：1

作者：

Dilday, Tinslee ^{[1
]}

Abt, Melissa ^{[1
]}

Ramos-Solis, Nicole ^{[1
]}

Dayal, Neetu ^{[4
,5
]}

Larocque, Elizabeth ^{[4
,5
]}

Oblak, Adrian L. ^{[3
]}

Sintim, Herman O. ^{[2
,4
,5
]}

Yeh, Elizabeth S. ^{[1
]}

机构：

[1] Indiana Univ Sch Med IUSM, Simon Canc Ctr, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA

[2] Purdue Univ, Dept Chem, Lafayette, IN 47907 USA

[3] IUSM, Dept Radiol & Imaging Sci, Indianapolis, IN 46202 USA

[4] Purdue Univ, Purdue Inst Drug Discovery, Lafayette, IN 47907 USA

[5] Purdue Univ, Purdue Inst Canc Res, Lafayette, IN 47907 USA

来源：

CELL CHEMICAL BIOLOGY | 2024年 / 31卷 / 05期

关键词：

CELL-SURVIVAL; KINASE; RESISTANCE; STAUROSPORINE; MECHANISMS; THERAPIES;

D O I：

10.1016/j.chembiol.2024.01.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as substrate of HUNK that is phosphorylated at serine (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both autophagy and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.

引用

页码：989 / 999.e7

页数：19

共 34 条

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