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A pharmacological approach identifies MAPK signalling inhibition as a key step in PHLDA1 reduction. MEK1/2 inhibition induces epigenetic changes at the PHLDA1 locus, including decreased H3Kme3 and H3K27ac. The class I HDAC inhibitor 4SC-202 restores PHLDA1 in lapatinib-resistant HER2+ breast cancer cells, and combined 4SC-202 with lapatinib yields synergistic growth suppression, suggesting prolonged lapatinib efficacy in patients.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/hdac-inhibition-restores-response-to-her2-targeted-therapy-in-breast-cancer-via-phlda1-induction/382263/",{"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/hdac-inhibition-restores-response-to-her2-targeted-therapy-in-breast-cancer-via-phlda1-induction/382263.png","ImageObject",300,407,{"name":92,"@type":93},"Ivy","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-25","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does PHLDA1 relate to resistance to HER2-targeted therapies?","Question",{"text":112,"@type":113},"PHLDA1 downregulation mediates resistance in receptor tyrosine kinase-driven cancers. Restoring PHLDA1 levels is presented as a strategy to counter resistance to RTK inhibitors such as lapatinib in HER2+ breast cancer.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which signalling pathway is identified as crucial for PHLDA1 downregulation?",{"text":117,"@type":113},"The study identifies inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation, with further experiments focusing on MEK1/2 inhibition.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the effect of combining 4SC-202 with lapatinib in HER2+ breast cancer cells?",{"text":121,"@type":113},"4SC-202 restores PHLDA1 expression in lapatinib-resistant HER2+ cells, and the combination of 4SC-202 and lapatinib produces synergistic effects on 2D cell proliferation and colony formation capacity.","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},382263,1790519989,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"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},549758252649,"https://ap-avatar.wpscdn.com/avatar/8000253669c5317157?_k=1778319167496531819","Article  \nHDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction  \nNatasha S. Clayton 1, Edward P. Carter 1, Abbie E. Fearon 1, James A. Heward 2, Luc½a Rodr½guez Fern¡ndez 1, Lina Boughetane 1, Edmund H. Wilkes 2, Pedro R. Cutillas 2 and Richard P. Grose 1, *,†  \n1 Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK  \n2 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK  \n* Correspondence: [r.p.grose@qmul.ac.uk](r.p.grose@qmul.ac.uk)  \n† Lead contact.  \nCitation: Clayton, N.S.; Carter, E.P.; Fearon, A.E.; Heward, J.A.;  \nRodríguez Fernández, L.; Boughetane, L.; Wilkes, E.H.; Cutillas, P.R.; Grose, R.P. HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction. Int. J. Mol. Sci. 2023, 24, 6228. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms24076228](10.3390/ijms24076228)  \nAcademic Editor: Nam Deuk Kim  \nReceived: 6 March 2023  \nRevised: 21 March 2023  \nAccepted: 23 March 2023  \nPublished: 25 March 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nAbstract: The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes atthe PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2+ breast cancer patients.  \nKeywords: PHLDA1; TDAG51; HER2; lapatinib; breast cancer; drug resistance  \n1. Introduction  \nBreast cancer has the second highest incidence of all cancer types worldwide and is the second most common cause of cancer death in women in the UK [1] . Approximately 15–20% of all breast cancer cases are characterised by the overexpression of human epidermal growth factor receptor-2 (HER2), which is associated with increased invasiveness and drug resistance [2] . A number of HER2-targeted therapies have been developed, including humanised monoclonal antibodies, tyrosine kinase inhibitors, and antibody–drug conjugates [3] . Although these anti-HER2 agents have been shown to significantly reduce disease recurrence when given in combination with chemotherapeutic agents, therapeutic resistance typically occurs within months of beginning treatment [4] . The reactivation of PI3K/AKT and MAPK signalling is thought to underpin resistance to HER2-targeted therapy [5] . However, strategies to circumvent this using combinations of PI3K-and MEK-targeted therapeutics have shown limited success due to severe dose-limiting toxicities [6] . Novel approaches are needed in order to safely circumvent resistance to anti-HER2 therapies.  \nWe previously identified that the downregulation of Pleckstrin Homology-Lik","cbCaisDA0DirfWm6","https://ap.wps.com/l/cbCaisDA0DirfWm6","pdf",2561417,14,"English","# Introduction\n## HER2-targeted therapy resistance and signalling pathways\n## PHLDA1 as a mediator of RTK-targeted therapy resistance\n## Regulation of PHLDA1 transcription by external stimuli and pathway activity","[{\"question\":\"How does PHLDA1 relate to resistance to HER2-targeted therapies?\",\"answer\":\"PHLDA1 downregulation mediates resistance in receptor tyrosine kinase-driven cancers. Restoring PHLDA1 levels is presented as a strategy to counter resistance to RTK inhibitors such as lapatinib in HER2+ breast cancer.\"},{\"question\":\"Which signalling pathway is identified as crucial for PHLDA1 downregulation?\",\"answer\":\"The study identifies inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation, with further experiments focusing on MEK1/2 inhibition.\"},{\"question\":\"What is the effect of combining 4SC-202 with lapatinib in HER2+ breast cancer cells?\",\"answer\":\"4SC-202 restores PHLDA1 expression in lapatinib-resistant HER2+ cells, and the combination of 4SC-202 and lapatinib produces synergistic effects on 2D cell proliferation and colony formation capacity.\"}]","HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction | PDF",1790249749,35]