Resistance to Trastuzumab
Sneha Vivekanandhan1, Keith L Knutson1
1Department of Immunology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
Abstract:
One of the most impactful biologics for the treatment of breast cancer is the humanized monoclonal antibody, trastuzumab, which specifically recognizes the HER2/neu (HER2) protein encoded by the ERBB2 gene. Useful for both advanced and early breast cancers, trastuzumab has multiple mechanisms of action. Classical mechanisms attributed to trastuzumab action include cell cycle arrest, induction of apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies have identified the role of the adaptive immune system in the clinical actions of trastuzumab. Despite the multiple mechanisms of action, many patients demonstrate resistance, primary or adaptive. Newly identified molecular and cellular mechanisms of trastuzumab resistance include induction of immune suppression, vascular mimicry, generation of breast cancer stem cells, deregulation of long non-coding RNAs, and metabolic escape. These newly identified mechanisms of resistance are discussed in detail in this review, particularly considering how they may lead to the development of well-rationalized, patient-tailored combinations that improve patient survival.
Insights
Trastuzumab is a key breast cancer biologic targeting HER2. This review explores new resistance mechanisms like immune suppression and metabolic escape, aiming for improved patient survival through tailored therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Trastuzumab is a critical biologic therapy for HER2-positive breast cancer.
- Its efficacy relies on multiple mechanisms, including ADCC and apoptosis induction.
- However, primary and adaptive resistance limit its clinical success.
Purpose of the Study:
- To review novel molecular and cellular mechanisms of trastuzumab resistance.
- To discuss how these resistance pathways can inform combination therapy strategies.
- To highlight potential avenues for improving patient survival in HER2-positive breast cancer.
Main Methods:
- Literature review of recent studies on trastuzumab resistance.
- Analysis of molecular and cellular pathways contributing to treatment failure.
- Synthesis of findings to propose future therapeutic approaches.
Main Results:
- Identified key resistance mechanisms: immune suppression, vascular mimicry, cancer stem cells, lncRNA deregulation, and metabolic escape.
- Highlighted the role of the adaptive immune system in trastuzumab action and resistance.
- Emphasized the heterogeneity of resistance pathways in breast cancer patients.
Conclusions:
- Understanding novel resistance mechanisms is crucial for overcoming therapeutic limitations.
- Developing patient-tailored combination therapies targeting these pathways can enhance treatment efficacy.
- Further research into these mechanisms promises to improve outcomes for breast cancer patients.
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