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Inhibiting HER3 Hyperphosphorylation in HER2-Overexpressing Breast Cancer through Multimodal Therapy with Branched
Eva Villar-Alvarez1, Irene Golán-Cancela2, Alberto Pardo1
1Grupo de Física de Coloides y Polímeros, Departamento de Física de la Materia Condensada, Universidad de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela IDIS, e Instituto de Materiales (IMATUS), Santiago de Compostela, 15782, Spain.
Abstract:
Treatment failure in breast cancers overexpressing human epidermal growth factor receptor 2 (HER2) is associated mainly to the upregulation of human epidermal growth factor receptor 3 (HER3) oncoprotein linked to chemoresitence. Therefore, to increase patient survival, here a multimodal theranostic nanoplatform targeting both HER2 and HER3 is developed. This consists of doxorubicin-loaded branched gold nanoshells functionalized with the near-infrared (NIR) fluorescent dye indocyanine green, a small interfering RNA (siRNA) against HER3, and the HER2-specific antibody Transtuzumab, able to provide a combined therapeutic outcome (chemo- and photothermal activities, RNA silencing, and immune response). In vitro assays in HER2+ /HER3+ SKBR-3 breast cancer cells have shown an effective silencing of HER3 by the released siRNA and an inhibition of HER2 oncoproteins provided by Trastuzumab, along with a decrease of the serine/threonine protein kinase Akt (p-AKT) typically associated with cell survival and proliferation, which helps to overcome doxorubicin chemoresistance. Conversely, adding the NIR light therapy, an increment in p-AKT concentration is observed, although HER2/HER3 inhibitions are maintained for 72 h. Finally, in vivo studies in a tumor-bearing mice model display a significant progressively decrease of the tumor volume after nanoparticle administration and subsequent NIR light irradiation, confirming the potential efficacy of the hybrid nanocarrier.
Insights
A novel nanoplatform targets both HER2 and HER3 in breast cancer, combining chemotherapy, photothermal therapy, and RNA silencing to overcome treatment resistance and reduce tumor volume effectively.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Treatment failure in HER2-overexpressing breast cancers is often linked to HER3 upregulation, causing chemoresistance.
- Targeting both HER2 and HER3 is crucial for improving patient survival rates.
Purpose of the Study:
- To develop a multimodal theranostic nanoplatform for targeting both HER2 and HER3 in breast cancer.
- To evaluate the combined therapeutic efficacy of chemotherapy, photothermal therapy, RNA silencing, and immune response.
Main Methods:
- A nanoplatform was engineered using doxorubicin-loaded gold nanoshells functionalized with indocyanine green, HER3-targeting siRNA, and Trastuzumab (anti-HER2 antibody).
- In vitro studies utilized HER2+/HER3+ SKBR-3 breast cancer cells to assess HER3 silencing, HER2 inhibition, and effects on p-AKT levels.
- In vivo studies involved a tumor-bearing mice model to evaluate the nanoplatform's efficacy in reducing tumor volume.
Main Results:
- In vitro assays demonstrated effective HER3 silencing and HER2 inhibition, leading to decreased p-AKT and overcoming doxorubicin resistance.
- Near-infrared (NIR) light therapy increased p-AKT but maintained HER2/HER3 inhibition for 72 hours.
- In vivo studies showed a significant reduction in tumor volume following nanoparticle administration and NIR irradiation.
Conclusions:
- The developed nanoplatform offers a promising multimodal therapeutic strategy for HER2-positive breast cancer.
- This theranostic approach effectively targets HER2 and HER3, overcoming chemoresistance and reducing tumor progression.
