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Trastuzumab doses fail to reach IC50 in intermediate-response models, where HER ligand release upregulation activates HER receptors. Inhibition of HER ligand shedding with a dual ADAM10/17 blocker shows only modest viability reduction, while neratinib works effectively alone and adds benefit with trastuzumab.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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Journal of Cancer  \nARTICLE OPEN   \nTranslational Therapeutics  \nNeratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models  \nMaryam Arshad 1,2,7, Abul Azad1,7, Phoebe Yuen Ka Chan1, Vasanthy Vigneswara2, Katharina Feldinger3, Siti Norasikin Mohd Nafi4, Eloise Laporte-Maguire 1, Carmela De Santo2, Jianmin Zuo 5, Abeer M. Shaaban 6 and Anthony Kong 1,2,3 ✉  \n© The Author(s) 2024  \n|  |  |  |\n| --- | --- | --- |\n|  | BACKGROUND: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear.\u003Cbr>METHODS: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatmentsin a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays. RESULTS: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab.\u003Cbr>CONCLUSION: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies. |  |  |\n|  | British Journal of Cancer (2024) 130:1990–2002; [https://doi.org/10.1038/s41416-024-02665-z](https://doi.org/10.1038/s41416-024-02665-z) |  |\n|  |  |  |\n\nINTRODUCTION  \nIn the era of precision medicine, Human Epidermal Growth Factor Receptor 2 (HER2) is the most important predictive and prognostic biomarker in breast cancer [1] . The assessment of HER2 status by immunohistochemistry (IHC) and/or in situ hybridization (ISH) is clinically essential to select appropriate patients for trastuzumaband/or other anti-HER2 treatments as guided by ASCO (American Society of Clinical Oncology) [2] . Patients with HER2 positive tumours (defined as IHC 3+ and/or HER2 copy number ≥ 6 if FISH/ CEP17 ratio \u003C2 and/or HER2 copy number ≥ 4 if FISH/CEP17 ratio ≥ 2) are usually recommended for treatment with trastuzumab and other anti-HER2 therapies. It was previously shown that HER2-positive (IHC 3 +) tumours were more likely to respond to trastuzumab and chemotherapy than those tumours with IHC 2+ or lower ( \u003C 2) scores [3] . However, there are some discrepancies in determining HER2 status by either IHC or FISH due to the use of different antibodies, staining platforms, and variation in cut off values for positivity [4]. The discrepancies have since improved with  \nthe introduction of the recent 2018 ASCO/CAP HER2 testing guideline. Due to this ambiguity in the classification of HER2 status previously, some patients with HER2-low tumours were found to benefit from anti-HER2 treatments in earlier studies. Paik et al.(2008) demonstrated that some patients with tumours originally identified as HER2 positive but later defined as HER2 negative by IHC/FISH score, also had improved survival outcomes from adjuvant trastuzumab containing treatment [5] . Moreover, the recent DESTINY-Breast04 trial showed that t","cbCaidD4EmENNjxU","https://ap.wps.com/l/cbCaidD4EmENNjxU","pdf",1163644,13,"English","# Background\n# Methods\n# Results\n# Conclusion\n# Introduction","[{\"question\":\"How did the study evaluate trastuzumab and combination strategies in HER2-low models?\",\"answer\":\"It investigated effects of trastuzumab alone and combined with different HER2 targeting treatments using biochemical methods and cell viability assays in breast cancer cell lines and patient-derived organoids.\"},{\"question\":\"Why did increasing trastuzumab doses fail to achieve IC50 in certain cell lines?\",\"answer\":\"Trastuzumab induced upregulation of HER ligand release, activating HER receptors in those HER2-low models, which may account for trastuzumab insensitivity.\"},{\"question\":\"What was the key finding regarding neratinib in HER2-low breast cancer cells and organoids?\",\"answer\":\"Neratinib showed effectiveness as monotherapy in HER2-low breast cancer cells and organoid models, and it produced additive effects when combined with trastuzumab.\"}]","Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models | PDF",1789990418,33]