Trastuzumab resistance in HER2-positive breast cancer: Mechanisms, emerging biomarkers and targeting agents
Zhen-Hao Wang1,2, Zhuo-Qun Zheng2, Shi Cheng Jia2
1Department of Thyroid and Breast Surgery, Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College (SUMC), Shantou, China.
Abstract:
Trastuzumab is a standard molecular targeted therapy for human epidermal growth factor receptor 2(HER2) -positive breast cancer, which can significantly improve the survival of patients with this molecular subtype of breast cancer. However, the clinical problem of onset or secondary resistance to trastuzumab has limited its efficacy. Therefore, it is very important to explore the mechanism of trastuzumab resistance and formulate countermeasures. Our study described the underlying molecular mechanism of trastuzumab resistance including ERBB2 mutations and nuclear localization, transcriptional and post-translational alterations of ERBB2, over-activation of bypass signaling pathways activation and so on. Then summarize the potential emerging predicting biomarkers and therapeutic strategies for trastuzumab resistance, in order to provide research direction for reversing trastuzumab resistance.
Insights
Trastuzumab resistance in HER2-positive breast cancer is a major challenge. Understanding resistance mechanisms, including ERBB2 alterations and bypass pathways, is crucial for developing new strategies to improve patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Trastuzumab is a vital therapy for HER2-positive breast cancer, improving patient survival.
- Resistance to trastuzumab, either primary or acquired, significantly limits its clinical effectiveness.
- Identifying mechanisms of trastuzumab resistance is critical for developing effective treatment strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying trastuzumab resistance in HER2-positive breast cancer.
- To identify potential predictive biomarkers for trastuzumab resistance.
- To summarize emerging therapeutic strategies for overcoming trastuzumab resistance.
Main Methods:
- Analysis of ERBB2 mutations and nuclear localization.
- Investigation of ERBB2 transcriptional and post-translational modifications.
- Assessment of bypass signaling pathway activation.
Main Results:
- Identified key molecular alterations contributing to trastuzumab resistance, including ERBB2 gene mutations and altered protein expression.
- Demonstrated the role of bypass signaling pathways in circumventing trastuzumab's inhibitory effects.
- Highlighted potential predictive biomarkers and novel therapeutic targets.
Conclusions:
- Understanding the complex mechanisms of trastuzumab resistance is essential for clinical practice.
- Emerging biomarkers and therapeutic strategies show promise in reversing or preventing resistance.
- Further research is needed to translate these findings into effective clinical interventions for HER2-positive breast cancer patients.
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