Dilday, TinsleeAbt, MelissaRamos-Solís, NicoleDayal, NeetuLarocque, ElizabethOblak, Adrian L.Sintim, Herman O.Yeh, Elizabeth S.2024-07-312024-07-312024Dilday T, Abt M, Ramos-Solís N, et al. Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer. Cell Chem Biol. 2024;31(5):989-999.e7. doi:10.1016/j.chembiol.2024.01.001https://hdl.handle.net/1805/42495Human 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.en-USPublisher PolicyHuman epidermal growth factor receptor 2 (HER2)HUNKRubiconAuthophagyBreast cancerIdentification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancerArticle