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

Sep 21, 2026

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HER2-targeted therapies improve outcomes, but resistance limits long-term benefit in HER2+ breast cancer. The study characterizes a selective HUNK inhibitor and evaluates a downstream phosphorylation event as a functional marker of HUNK activity. Rubicon is identified as a HUNK substrate phosphorylated at serine 92, and HUNK-mediated Rubicon S92 phosphorylation promotes autophagy and tumorigenesis in HER2/neu+ models. HUNK inhibition blocks Rubicon S92 phosphorylation and suppresses tumorigenesis, supporting HUNK activity readout and inhibitor efficacy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages31

Reading Time1 h 18 min

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Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Cell Chem Biol. Author manuscript; available in PMC 2024 May 19. | | --- | --- | Published in final edited form as: Cell Chem Biol. 2024 May 16; 31(5): 989–999.e7. doi:10.1016/j.chembiol.2024.01.001 . Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer Tinslee Dilday 1 , Melissa Abt 1 , Nicole Ramos-Solís 1 , Neetu Dayal4 , Elizabeth Larocque4 , Adrian L. Oblak3 , Herman O. Sintim2,4 , Elizabeth S. Yeh 1,5,* 1 Department of Pharmacology and Toxicology, Indiana University School of Medicine (IUSM), Simon Cancer Center, Indianapolis, IN 46202, USA 2 Department of Chemistry, Purdue University, Lafayette, IN 47907, USA 3 Department of Radiology and Imaging Sciences, IUSM, Indianapolis, IN 46202, USA 4 Purdue Institute for Drug Discovery and Purdue Institute for Cancer Research, Purdue University, Lafayette, IN 47907, USA 5Lead contact SUMMARY 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. Graphical abstract This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). *Correspondence: [esyeh@iu.edu](esyeh@iu.edu). AUTHOR CONTRIBUTIONS Conceptualization and methodology, T.D., E.S.Y., and H.O.S. Validation and formal analysis, T.D., A.L.O., N.D., E.L., and E.S.Y. Writing – original draft, T.D. and E.S.Y. Writing – review and editing, T.D., E.S.Y., H.O.S., M.A., N.D., and N.R.S. Investigation, T.D., M.A., N.R.S., N.D., and E.L. Resources, E.S.Y., H.O.S., and A.L.O. Supervision and funding acquisition, E.S.Y. and H.O.S. SUPPLEMENTAL INFORMATION Supplemental information can be found online at [https://doi.org/10.1016/j.chembiol.2024.01.001](https://doi.org/10.1016/j.chembiol.2024.01.001) . DECLARATION OF INTERESTS H.O. Sintim has a patent for US11001559B2 issued and licensed to KinaRx Inc. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Dilday et al. Page 2 In brief Dilday et al. show that a newly synthesized chemical compound inhibits HUNK activity. Targeting HUNK activity leads to reduced phosphorylation of the HUNK substrate Rubicon, impairing autophagy, and cell survival, resulting in reduced tumorigenesis in HER2+ breast cancer models. INTRODUCTION HER2 positive (HER2+) breast cancer is a type of breast cancer that has overexpression of HER2 protein alongside HER2 gene amplification. HER2+ breast cancer makes up around 15–30% of breast cancer and is associated with poor patient outcomes.1 Multiple HER2 inhibitors have been developed for the treatment of HER2+ breast cancer, however, resistance to these inhibitors develops over time. There are also multiple mechanisms of resistance such as alterations to HER2, mutations in downstream signaling pathways, and activation of bypass signaling pathways.2 Therefore, evalua

FAQs

Why is targeting HUNK relevant in HER2+ breast cancer?

HUNK is upregulated in HER2+ breast cancer and supports tumorigenic phenotypes, including cell survival, and has evidence linking it to resistance against HER2 inhibitors.

What phosphorylation event is used as a marker of HUNK activity?

Rubicon is phosphorylated at serine 92 (S92) by HUNK, and Rubicon S92 phosphorylation is presented as an activity marker.

How does inhibiting HUNK affect autophagy and tumorigenesis?

HUNK inhibition prevents Rubicon S92 phosphorylation and impairs autophagy and cell survival, resulting in reduced tumorigenesis in HER2+ breast cancer models.

Sep 21, 2026

Uploaded by Eliana