Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer
M S N Mohd Sharial1, J Crown2, B T Hennessy1
1Department of Medical Oncology, Beaumont Hospital, Dublin; Our Lady of Lourdes Hospital, Drogheda.
Background:
Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.
Design:
A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease.
Results:
Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer.
Conclusions:
Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.
Insights
Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy in breast cancer is common. Novel non-HER2 targeted therapies, such as mTOR inhibitors, show promise for overcoming this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), driving proliferation.
- HER2-targeted therapies improve outcomes but face de novo and acquired resistance.
- Understanding resistance mechanisms is crucial for developing effective treatments.
Purpose of the Study:
- To identify proposed mechanisms of resistance to HER2-targeted therapy.
- To identify novel therapeutic targets for HER2-resistant breast cancer.
Main Methods:
- Literature search for HER2 resistance mechanisms.
- Literature search for novel therapeutic targets in clinical development.
Main Results:
- Resistance mechanisms include impaired HER2-inhibitor binding, alternative pathway signaling, downstream pathway upregulation, and immune response failure.
- Targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway is a promising strategy.
- The mTOR inhibitor everolimus shows activity in trastuzumab-refractory advanced breast cancer.
Conclusions:
- Non-HER2 targeted therapies offer a promising approach to overcome HER2 resistance.
- Ongoing clinical studies will further evaluate novel targeted therapies for HER2-resistant breast cancer.
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