99mTc-HP-Ark2 SPECT/CT imaging reveals dynamic HER2 regulation in trastuzumab resistance and its reversal by PI3K
Xiuting Lin1,2, Zhenying Chen1,2, Junyu Lin3
1Department of Nuclear Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China.
Abstract:
Trastuzumab is a first-line treatment for human epidermal growth receptor 2 (HER2)-positive breast cancer, but resistance severely limits its efficacy, with underlying mechanisms involving HER2 expression still requiring further elucidation. This study aimed to investigate the dynamic changes in HER2 expression during the development and reversal of trastuzumab resistance, and to evaluate the utility of a novel HER2-targeting molecular probe, 99mTc-HP-Ark2, for non-invasive, real-time monitoring of HER2 status and treatment response. Trastuzumab-resistant SK-BR-3R cells, established through chronic exposure of parental SK-BR-3 cells to increasing concentrations of trastuzumab, exhibited stable resistance (resistance index = 13.79), accompanied by significant upregulation of HER2 and phosphorylated PI3K (p-PI3K) expression. Treatment with the PI3K inhibitor LY294002 effectively inhibited p-PI3K activation and substantially reduced HER2 expression. Notably, the combination of LY294002 with trastuzumab led to a more pronounced downregulation of HER2 and restored trastuzumab sensitivity in SK-BR-3R cells. In vivo SPECT/CT imaging consistently showed significantly higher 99mTc-HP-Ark2 uptake in SK-BR-3R tumors compared to SK-BR-3 tumors, which markedly decreased upon treatment with LY294002 alone or in combination with trastuzumab. Immunohistochemistry (IHC) analysis confirmed a strong positive correlation between changes in HER2 expression and tumor radioactive uptake trends. This study highlights the pivotal role of HER2 as a dynamic biomarker in trastuzumab resistance and supports the integration of molecular imaging into clinical decision-making for personalized therapeutic adjustments in HER2-positive breast cancer.
Insights
Trastuzumab resistance in HER2-positive breast cancer involves dynamic HER2 changes. A novel probe, 99mTc-HP-Ark2, non-invasively monitors HER2 status and treatment response, aiding personalized therapy.
Area of Science:
- Oncology
- Molecular Imaging
- Biochemistry
Background:
- Trastuzumab is a key treatment for HER2-positive breast cancer.
- Resistance to trastuzumab limits its effectiveness, with HER2 expression dynamics needing clarification.
Purpose of the Study:
- Investigate dynamic HER2 expression changes during trastuzumab resistance development and reversal.
- Evaluate 99mTc-HP-Ark2 for non-invasive, real-time HER2 status and treatment response monitoring.
Main Methods:
- Established trastuzumab-resistant SK-BR-3R cells.
- Treated cells and tumors with PI3K inhibitor LY294002 and trastuzumab.
- Utilized in vivo SPECT/CT imaging with 99mTc-HP-Ark2.
- Performed immunohistochemistry (IHC) analysis.
Main Results:
- Resistant cells showed HER2 and p-PI3K upregulation.
- LY294002 inhibited p-PI3K, reduced HER2, and restored sensitivity when combined with trastuzumab.
- SPECT/CT imaging revealed higher 99mTc-HP-Ark2 uptake in resistant tumors, decreasing with treatment.
- IHC confirmed correlation between HER2 expression and tumor uptake.
Conclusions:
- HER2 is a dynamic biomarker in trastuzumab resistance.
- Molecular imaging with 99mTc-HP-Ark2 can monitor HER2 status and treatment response.
- This supports personalized therapy adjustments in HER2-positive breast cancer.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
