,
Cheng Liao,
Zeyun Xue,
Yimei Sun,
Ying Chen,
Xin Liu,
David MacEwan,
Lianshan Zhang,
Mu Wang*
Background: In recent years, the therapeutic landscape for cancer patients has undergone a profound transformation with the emergence of third-generation HER2-targeted ADCs, including T-DXd and SHR-A1811. Nevertheless, recurrence and metastasis are inevitable for most patients, and the mechanisms driving resistance to these ADCs remain poorly understood. Against this backdrop, the present study seeks to elucidate the resistance mechanisms of breast cancer cells to SHR-A1811 and T-DXd, while identifying potential targets to enhance sensitivity to these agents. Methods: Two resistant cell lines-SHR-A1811-resistant and T-DXd-resistant-were established from the parental breast cancer JIMT-1 cell line via successive drug administration. To identify alterations in protein expression profiles, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and single-cell RNA sequencing (scRNA-seq) were employed. Validation of the findings was performed using Western blotting, RNA interference, transfection, and the CellTiter-Glo (CTG) Luminescent Cell Viability Assay. Results: A total of 5,664 differentially expressed proteins were quantitatively identified via proteomic analysis comparing SHR-A1811/T-DXd-resistant cells with their sensitive counterparts. Integrated proteomic and scRNA-seq analyses revealed significant up-regulation of CD44 and PLOD2 in resistant cells. Subsequent validation studies confirmed that CD44 expression was substantially higher in both resistant cells relative to their sensitive counterparts, and CD44 knockdown enhanced the sensitivity of the resistant cells to the ADCs. Conclusions: Our findings demonstrate that CD44 is a critical factor in the development of resistance to SHR-A1811 and T-DXd, with potential utility as both a resistance biomarker for third-generation HER2-ADCs in breast cancer and a therapeutic target to overcome such resistance.
| Published in | International Journal of Clinical Oncology and Cancer Research (Volume 10, Issue 4) |
| DOI | 10.11648/j.ijcocr.20251004.18 |
| Page(s) | 177-189 |
| Creative Commons |
This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited. |
| Copyright |
Copyright © The Author(s), 2025. Published by Science Publishing Group |
SHR-A1811, T-DXd, HER2-ADC, Resistance Mechanism, Proteomic Analysis, sc-RNA-seq Analysis
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APA Style
Rong, S., Liao, C., Xue, Z., Sun, Y., Chen, Y., et al. (2025). Mechanistic Investigation of Resistance to SHR-A1811 and T-DXd, the Third Generation of HER2-ADC, in Breast Cancer. International Journal of Clinical Oncology and Cancer Research, 10(4), 177-189. https://doi.org/10.11648/j.ijcocr.20251004.18
ACS Style
Rong, S.; Liao, C.; Xue, Z.; Sun, Y.; Chen, Y., et al. Mechanistic Investigation of Resistance to SHR-A1811 and T-DXd, the Third Generation of HER2-ADC, in Breast Cancer. Int. J. Clin. Oncol. Cancer Res. 2025, 10(4), 177-189. doi: 10.11648/j.ijcocr.20251004.18
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Download@article{10.11648/j.ijcocr.20251004.18,
author = {Shangyi Rong and Cheng Liao and Zeyun Xue and Yimei Sun and Ying Chen and Xin Liu and David MacEwan and Lianshan Zhang and Mu Wang},
title = {Mechanistic Investigation of Resistance to SHR-A1811 and T-DXd, the Third Generation of HER2-ADC, in Breast Cancer},
journal = {International Journal of Clinical Oncology and Cancer Research},
volume = {10},
number = {4},
pages = {177-189},
doi = {10.11648/j.ijcocr.20251004.18},
url = {https://doi.org/10.11648/j.ijcocr.20251004.18},
eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijcocr.20251004.18},
abstract = {Background: In recent years, the therapeutic landscape for cancer patients has undergone a profound transformation with the emergence of third-generation HER2-targeted ADCs, including T-DXd and SHR-A1811. Nevertheless, recurrence and metastasis are inevitable for most patients, and the mechanisms driving resistance to these ADCs remain poorly understood. Against this backdrop, the present study seeks to elucidate the resistance mechanisms of breast cancer cells to SHR-A1811 and T-DXd, while identifying potential targets to enhance sensitivity to these agents. Methods: Two resistant cell lines-SHR-A1811-resistant and T-DXd-resistant-were established from the parental breast cancer JIMT-1 cell line via successive drug administration. To identify alterations in protein expression profiles, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and single-cell RNA sequencing (scRNA-seq) were employed. Validation of the findings was performed using Western blotting, RNA interference, transfection, and the CellTiter-Glo (CTG) Luminescent Cell Viability Assay. Results: A total of 5,664 differentially expressed proteins were quantitatively identified via proteomic analysis comparing SHR-A1811/T-DXd-resistant cells with their sensitive counterparts. Integrated proteomic and scRNA-seq analyses revealed significant up-regulation of CD44 and PLOD2 in resistant cells. Subsequent validation studies confirmed that CD44 expression was substantially higher in both resistant cells relative to their sensitive counterparts, and CD44 knockdown enhanced the sensitivity of the resistant cells to the ADCs. Conclusions: Our findings demonstrate that CD44 is a critical factor in the development of resistance to SHR-A1811 and T-DXd, with potential utility as both a resistance biomarker for third-generation HER2-ADCs in breast cancer and a therapeutic target to overcome such resistance.},
year = {2025}
}
TY - JOUR T1 - Mechanistic Investigation of Resistance to SHR-A1811 and T-DXd, the Third Generation of HER2-ADC, in Breast Cancer AU - Shangyi Rong AU - Cheng Liao AU - Zeyun Xue AU - Yimei Sun AU - Ying Chen AU - Xin Liu AU - David MacEwan AU - Lianshan Zhang AU - Mu Wang Y1 - 2025/12/29 PY - 2025 N1 - https://doi.org/10.11648/j.ijcocr.20251004.18 DO - 10.11648/j.ijcocr.20251004.18 T2 - International Journal of Clinical Oncology and Cancer Research JF - International Journal of Clinical Oncology and Cancer Research JO - International Journal of Clinical Oncology and Cancer Research SP - 177 EP - 189 PB - Science Publishing Group SN - 2578-9511 UR - https://doi.org/10.11648/j.ijcocr.20251004.18 AB - Background: In recent years, the therapeutic landscape for cancer patients has undergone a profound transformation with the emergence of third-generation HER2-targeted ADCs, including T-DXd and SHR-A1811. Nevertheless, recurrence and metastasis are inevitable for most patients, and the mechanisms driving resistance to these ADCs remain poorly understood. Against this backdrop, the present study seeks to elucidate the resistance mechanisms of breast cancer cells to SHR-A1811 and T-DXd, while identifying potential targets to enhance sensitivity to these agents. Methods: Two resistant cell lines-SHR-A1811-resistant and T-DXd-resistant-were established from the parental breast cancer JIMT-1 cell line via successive drug administration. To identify alterations in protein expression profiles, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and single-cell RNA sequencing (scRNA-seq) were employed. Validation of the findings was performed using Western blotting, RNA interference, transfection, and the CellTiter-Glo (CTG) Luminescent Cell Viability Assay. Results: A total of 5,664 differentially expressed proteins were quantitatively identified via proteomic analysis comparing SHR-A1811/T-DXd-resistant cells with their sensitive counterparts. Integrated proteomic and scRNA-seq analyses revealed significant up-regulation of CD44 and PLOD2 in resistant cells. Subsequent validation studies confirmed that CD44 expression was substantially higher in both resistant cells relative to their sensitive counterparts, and CD44 knockdown enhanced the sensitivity of the resistant cells to the ADCs. Conclusions: Our findings demonstrate that CD44 is a critical factor in the development of resistance to SHR-A1811 and T-DXd, with potential utility as both a resistance biomarker for third-generation HER2-ADCs in breast cancer and a therapeutic target to overcome such resistance. VL - 10 IS - 4 ER -
Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China;Department of Oncology Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
Department of Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
Department of Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
Department of Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
Department of Oncology Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China;Department of Research & Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, China
Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University, Suzhou, China
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