HER3 PET Imaging Identifies Dynamic Changes in HER3 in Response to HER2 Inhibition with Lapatinib
Eric Wehrenberg-Klee1, Nicoleta Sinevici1, Sarah Nesti1
1Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, 149 13th Street, Suite 5.407, Boston, MA, 02129, USA.
Purpose:
Standard therapy for HER2+ breast cancers includes HER2 inhibition. While HER2 inhibitors have significantly improved therapeutic outcomes, many patients remain resistant to therapy. An important intrinsic resistance mechanism to HER2 inhibition in some breast cancers is dynamic upregulation of HER3. Increase in HER3 expression that occurs in response to HER2 inhibition allows for continued growth signaling through HER2/HER3 heterodimers, promoting tumor escape. We hypothesized that a non-invasive method to image changes in HER3 expression would be valuable to identify those breast cancers that dynamically upregulate HER3 in response to HER2 inhibition. We further hypothesized that this imaging method could identify those tumors that would benefit by additional HER3 knockdown.
Procedures:
In a panel of HER2+ breast cancer cell lines treated with the HER2 inhibitor lapatinib, we evaluate changes in HER3 expression and viability. Mouse HER2+ breast cancer models treated with lapatinib were imaged with a peptide-based HER3-specific PET imaging agent [68Ga]HER3P1 to assess for dynamic changes in tumoral HER3 expression and uptake confirmed by biodistribution. Subsequently, HER2+ cell lines were treated with the HER2 inhibitor lapatinib as well HER3-specific siRNA to assess for changes in viability and correlate with HER3 expression upregulation. For all statistical comparisons, P<0.05 was considered statistically significant.
Results:
Lapatinib treatment of a panel of HER2+ breast cancer cell lines increased HER3 expression in the lapatinib-resistant cell line MDA-MB 453 but not the lapatinib-resistant cell-line HCC-1569. Evaluation of [68Ga]HER3P1 uptake in mice implanted with the HER2+ breast cancer cell lines MDA-MB453 or HCC-1569 prior to and after treatment with lapatinib demonstrated a significant increase in MDA-MB453 tumors only, consistent with in vitro findings. The additional knockdown of HER3 increased therapeutic efficacy of lapatinib only in MDA-MB453 cells, but not in HCC-1569 cells.
Conclusion:
HER3 PET imaging can be used to visualize dynamic changes in HER3 expression that occur in HER2+ breast cancers with HER2 inhibitor treatment and identify those likely to benefit by the addition of combination HER3 and HER2 inhibition.
Insights
New PET imaging can identify HER2+ breast cancers that resist HER2 inhibition by upregulating HER3. This imaging approach helps pinpoint tumors that may benefit from combined HER2 and HER3 targeted therapies.
Area of Science:
- Oncology
- Molecular Imaging
- Biotechnology
Background:
- Standard treatment for HER2-positive (HER2+) breast cancer involves HER2 inhibition, but therapeutic resistance remains a challenge.
- Upregulation of HER3 is a key mechanism of intrinsic resistance to HER2 inhibitors in some breast cancers, allowing continued tumor growth.
- Developing non-invasive methods to monitor HER3 expression changes is crucial for optimizing treatment strategies.
Purpose of the Study:
- To evaluate a novel peptide-based positron emission tomography (PET) imaging agent, [68Ga]HER3P1, for visualizing dynamic changes in HER3 expression in HER2+ breast cancer models.
- To determine if HER3 PET imaging can identify breast tumors that exhibit increased HER3 expression in response to HER2 inhibition.
- To assess whether this imaging approach can predict which tumors would benefit from additional HER3 knockdown therapy.
Main Methods:
- HER2+ breast cancer cell lines and mouse models were treated with the HER2 inhibitor lapatinib.
- Changes in HER3 expression and cell viability were assessed in vitro.
- PET imaging using [68Ga]HER3P1 was performed on mice before and after lapatinib treatment to evaluate tumoral HER3 uptake.
- HER3 knockdown using siRNA was combined with lapatinib treatment to assess therapeutic efficacy.
Main Results:
- Lapatinib treatment increased HER3 expression in the MDA-MB-453 cell line but not in the HCC-1569 cell line.
- [68Ga]HER3P1 PET imaging showed a significant increase in tracer uptake in MDA-MB-453 tumors after lapatinib treatment, consistent with in vitro findings.
- Combined HER3 knockdown and lapatinib treatment enhanced therapeutic efficacy only in MDA-MB-453 cells, indicating a role for HER3 in resistance.
Conclusions:
- HER3-specific PET imaging with [68Ga]HER3P1 can effectively visualize dynamic changes in HER3 expression in HER2+ breast cancers during HER2 inhibitor therapy.
- This imaging modality can identify tumors likely to develop resistance through HER3 upregulation.
- HER3 PET imaging may guide treatment decisions, identifying patients who could benefit from combination therapy targeting both HER2 and HER3.
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