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HER2-family signalling mechanisms, clinical implications and targeting in breast cancer
N Elster1, D M Collins, S Toomey
1Department of Medical Oncology, Molecular Medicine Laboratories, ERC Smurift Building, Royal College of Surgeons in Ireland, Dublin, Ireland.
Abstract:
Approximately 20 % of human breast cancers (BC) overexpress HER2 protein, and HER2-positivity is associated with a worse prognosis. Although HER2-targeted therapies have significantly improved outcomes for HER2-positive BC patients, resistance to trastuzumab-based therapy remains a clinical problem. In order to better understand resistance to HER2-targeted therapies in HER2-positive BC, it is necessary to examine HER family signalling as a whole. An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in HER2-positive BC and response to HER2-targeted therapy. Known mechanisms of trastuzumab resistance include reduced receptor-antibody binding (MUC4, p95HER2), increased signalling through alternative HER family receptor tyrosine kinases (RTK), altered intracellular signalling involving loss of PTEN, reduced p27kip1, or increased PI3K/AKT activity and altered signalling via non-HER family RTKs such as IGF1R. Emerging strategies to circumvent resistance to HER2-targeted therapies in HER2-positive BC include co-targeting HER2/PI3K, pan-HER family inhibition, and novel therapies such as T-DM1. There is evidence that immunity plays a key role in the efficacy of HER-targeted therapy, and efforts are being made to exploit the immune system in order to improve the efficacy of current anti-HER therapies. With our rapidly expanding understanding of HER2 signalling mechanisms along with the repertoire of HER family and other targeted therapies, it is likely that the near future holds further dramatic improvements to the prognosis of women with HER2-positive BC.
Insights
Understanding HER2-targeted therapy resistance in breast cancer (BC) is crucial. Research explores HER family signaling mechanisms and novel strategies to overcome resistance, aiming to improve outcomes for HER2-positive BC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- HER2-positive breast cancer (BC) accounts for approximately 20% of human BC cases.
- HER2-positivity is linked to a poorer prognosis, despite advancements in HER2-targeted therapies.
- Resistance to trastuzumab-based therapy presents a significant clinical challenge in HER2-positive BC.
Purpose of the Study:
- To critically assess current knowledge of HER family signaling in HER2-positive BC.
- To understand the mechanisms of resistance to HER2-targeted therapies.
- To explore emerging strategies for overcoming treatment resistance.
Main Methods:
- Extensive literature search and critical assessment of existing research.
- Analysis of known mechanisms of trastuzumab resistance.
- Review of novel therapeutic strategies and the role of immunity.
Main Results:
- Mechanisms of resistance include altered receptor-antibody binding (e.g., MUC4, p95HER2), activation of alternative HER family or non-HER family receptor tyrosine kinases (e.g., IGF1R), and dysregulated intracellular signaling (e.g., PTEN loss, PI3K/AKT activation).
- Emerging strategies involve co-targeting HER2/PI3K, pan-HER family inhibition, and novel agents like T-DM1.
- Immune system involvement in HER-targeted therapy efficacy is recognized, with efforts to leverage immunity.
Conclusions:
- A comprehensive understanding of HER family signaling is essential for addressing resistance in HER2-positive BC.
- Novel therapeutic approaches and immunotherapies hold promise for improving treatment outcomes.
- Continued research into HER2 signaling and targeted therapies is expected to significantly enhance the prognosis for patients with HER2-positive BC.
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