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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.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/identification-and-characterization-of-a-potent-and-selective-hunk-inhibitor-for-treatment-of-her2-breast-cancer/330648/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/identification-and-characterization-of-a-potent-and-selective-hunk-inhibitor-for-treatment-of-her2-breast-cancer/330648.png","ImageObject",300,407,{"name":92,"@type":93},"Eliana","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is targeting HUNK relevant in HER2+ breast cancer?","Question",{"text":112,"@type":113},"HUNK is upregulated in HER2+ breast cancer and supports tumorigenic phenotypes, including cell survival, and has evidence linking it to resistance against HER2 inhibitors.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What phosphorylation event is used as a marker of HUNK activity?",{"text":117,"@type":113},"Rubicon is phosphorylated at serine 92 (S92) by HUNK, and Rubicon S92 phosphorylation is presented as an activity marker.",{"name":119,"@type":110,"acceptedAnswer":120},"How does inhibiting HUNK affect autophagy and tumorigenesis?",{"text":121,"@type":113},"HUNK inhibition prevents Rubicon S92 phosphorylation and impairs autophagy and cell survival, resulting in reduced tumorigenesis in HER2+ breast cancer models.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},330648,1790193595,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},4398048949847,"https://ap-avatar.wpscdn.com/avatar/400002536579ef2da7f?_k=1778318612642679267","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Cell Chem Biol. Author manuscript; available in PMC 2024 May 19. |\n| --- | --- |\n\nPublished in final edited form as:  \nCell Chem Biol. 2024 May 16; 31(5): 989–999.e7. doi:10.1016/j.chembiol.2024.01.001 .  \nIdentification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer  \nTinslee 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,*  \n1 Department of Pharmacology and Toxicology, Indiana University School of Medicine (IUSM), Simon Cancer Center, Indianapolis, IN 46202, USA  \n2 Department of Chemistry, Purdue University, Lafayette, IN 47907, USA  \n3 Department of Radiology and Imaging Sciences, IUSM, Indianapolis, IN 46202, USA  \n4 Purdue Institute for Drug Discovery and Purdue Institute for Cancer Research, Purdue University, Lafayette, IN 47907, USA  \n5Lead contact  \nSUMMARY  \nHuman 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.  \nGraphical abstract  \nThis 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/)).  \n*Correspondence: [esyeh@iu.edu](esyeh@iu.edu).  \nAUTHOR CONTRIBUTIONS  \nConceptualization 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.  \nSUPPLEMENTAL INFORMATION  \nSupplemental 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) .  \nDECLARATION OF INTERESTS  \nH.O. Sintim has a patent for US11001559B2 issued and licensed to KinaRx Inc.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nDilday et al.  \nPage 2  \nIn brief  \nDilday 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.  \nINTRODUCTION  \nHER2 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","cbCaioipeMhR6Uoc","https://ap.wps.com/l/cbCaioipeMhR6Uoc","pdf",1086493,31,"English","# Summary\n# In brief\n# Introduction","[{\"question\":\"Why is targeting HUNK relevant in HER2+ breast cancer?\",\"answer\":\"HUNK is upregulated in HER2+ breast cancer and supports tumorigenic phenotypes, including cell survival, and has evidence linking it to resistance against HER2 inhibitors.\"},{\"question\":\"What phosphorylation event is used as a marker of HUNK activity?\",\"answer\":\"Rubicon is phosphorylated at serine 92 (S92) by HUNK, and Rubicon S92 phosphorylation is presented as an activity marker.\"},{\"question\":\"How does inhibiting HUNK affect autophagy and tumorigenesis?\",\"answer\":\"HUNK inhibition prevents Rubicon S92 phosphorylation and impairs autophagy and cell survival, resulting in reduced tumorigenesis in HER2+ breast cancer models.\"}]","Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer | PDF",1789989630,78]