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

Tinslee Dilday; Melissa Abt; Nicole Ramos-Solís; Neetu Dayal; Elizabeth Larocque; Adrian L Oblak; Herman O Sintim; Elizabeth S Yeh

doi:10.1016/j.chembiol.2024.01.001

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

Cell Chem Biol. 2024 May 16;31(5):989-999.e7. doi: 10.1016/j.chembiol.2024.01.001. Epub 2024 Feb 1.

Authors

Tinslee Dilday¹, Melissa Abt¹, Nicole Ramos-Solís¹, Neetu Dayal², Elizabeth Larocque², Adrian L Oblak³, Herman O Sintim⁴, Elizabeth S Yeh⁵

Affiliations

¹ Department of Pharmacology and Toxicology, Indiana University School of Medicine (IUSM), Simon Cancer Center, Indianapolis, IN 46202, USA.
² Purdue Institute for Drug Discovery and Purdue Institute for Cancer Research, Purdue University, Lafayette, IN 47907, USA.
³ Department of Radiology and Imaging Sciences, IUSM, Indianapolis, IN 46202, USA.
⁴ Department of Chemistry, Purdue University, Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery and Purdue Institute for Cancer Research, Purdue University, Lafayette, IN 47907, USA.
⁵ Department of Pharmacology and Toxicology, Indiana University School of Medicine (IUSM), Simon Cancer Center, Indianapolis, IN 46202, USA. Electronic address: [email protected].

Abstract

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 a 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.

Keywords: HER2; HUNK; Rubicon; authophagy; breast cancer.

MeSH terms

Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Autophagy-Related Proteins / drug effects
Breast Neoplasms* / drug therapy
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Humans
Mice
Mice, Nude
Phosphorylation / drug effects
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Protein Serine-Threonine Kinases* / antagonists & inhibitors
Receptor, ErbB-2* / antagonists & inhibitors
Receptor, ErbB-2* / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
ERBB2 protein, human
Receptor, ErbB-2
HUNK protein, human
Protein Serine-Threonine Kinases
Protein Kinase Inhibitors
RUBCN protein, human
Autophagy-Related Proteins

Abstract

MeSH terms

Substances

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