Kinase Plasticity in Response to Vandetanib Enhances Sensitivity to Tamoxifen in Estrogen Receptor Positive Breast Cancer.

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.

Significance: Vandetanib enhances sensitivity to tamoxifen in ER+ breast cancer cells by reprograming kinase signaling networks, which can be used to select patients most likely to respond and develop more efficacious co-treatment strategies.