Kinase Plasticity in Response to Vandetanib Enhances Sensitivity to Tamoxifen in Estrogen Receptor Positive Breast
Rasha T Kakati1, Austin A Whitman1, Santiago Haase1
1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
Abstract:
Resistance to endocrine therapy (ET) is common in estrogen receptor (ER) positive breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment enhances sensitivity to ET in ET-sensitive and -resistant ER+ breast cancer models. Vandetanib treatment alters the gene expression program of ER+ breast cancer cells resulting in a less proliferative and more estrogen responsive Luminal-A like character. Tyrosine kinase network reprogramming was assessed using multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) assay to identify adaptive resistance mechanisms to vandetanib treatment, including upregulation of HER2 activity. Co-treatment to inhibit HER2 with lapatinib enhanced sensitivity to vandetanib, demonstrating biologic activity of HER2 upregulation. Using a CRISPR knockout model, we demonstrate that vandetanib effects are partially mediated by RET receptor tyrosine kinase. Finally, we use our operating room-to-laboratory assay that measures drug response in individual primary tumor cells in short term cultures to demonstrate conserved gene expression changes, including increased HER2 activity signatures, in vandetanib treated cells, and identify features associated with vandetanib response. These results support future investigation of RET targeting strategies considering reprogrammed networks, such as activated HER2, in patients with ET resistant ER+ breast cancer.
Insights
Vandetanib enhances endocrine therapy sensitivity in estrogen receptor-positive breast cancer by altering gene expression. This study identifies HER2 and RET as key targets for overcoming resistance to endocrine therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Endocrine therapy (ET) resistance is a major challenge in estrogen receptor (ER)-positive breast cancer.
- Upregulation of MAPK signaling pathways is a known mechanism contributing to ET resistance.
Purpose of the Study:
- To investigate the efficacy of vandetanib in overcoming ET resistance in ER+ breast cancer.
- To identify molecular mechanisms and adaptive resistance pathways involved in vandetanib treatment.
Main Methods:
- Utilized ER+ breast cancer models (in vitro and ex vivo primary cells).
- Assessed gene expression changes and tyrosine kinase network reprogramming using multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS).
- Employed CRISPR knockout models and an operating room-to-laboratory assay for drug response evaluation.
Main Results:
- Vandetanib treatment enhanced sensitivity to ET in both sensitive and resistant ER+ breast cancer models.
- Vandetanib altered gene expression towards a less proliferative, Luminal-A-like phenotype.
- Adaptive resistance mechanisms included HER2 activity upregulation, which was targeted by lapatinib co-treatment.
- RET receptor tyrosine kinase partially mediated vandetanib's effects.
- Ex vivo assays confirmed conserved gene expression changes and identified features associated with vandetanib response.
Conclusions:
- Vandetanib shows promise in enhancing ET sensitivity in ER+ breast cancer.
- Targeting RET and considering adaptive HER2 activation are potential strategies for overcoming ET resistance.
- Further investigation of RET-targeting strategies in combination with therapies addressing reprogrammed networks like HER2 is warranted for patients with ET-resistant breast cancer.
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