Kinase Plasticity with Vandetanib Treatment Enhances Sensitivity to Tamoxifen in Estrogen Receptor Positive Breast Cancer

作者：Austin A. Whitman, Rasha T. Kakati, Santiago Haase, Christine Thai, Surya Kant Tripathi, Attila T. Szenasi, Elizabeth Brunk, Denis O. Okumu, Michael P. East, Sarahi G. Molina, Adriana S. Beltrán, Jesse R. Raab, Lisa A. Carey, Charles M. Perou, Gary L. Johnson, Philip M. Spanheimer · 发表于：Molecular Cancer Therapeutics · 年份：2026 · DOI：10.1158/1535-7163.mct-26-0063 · 研究领域：Advanced Breast Cancer Therapies、Estrogen and related hormone effects、Breast Cancer Treatment Studies

Resistance to endocrine therapy (ET) is common in estrogen receptor-positive (ER+) breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment suppresses MAPK signaling and enhances sensitivity to ET across ET-sensitive and ET-resistant ER+ cell lines and patient derived organoids. Vandetanib treatment reprograms transcription toward a less proliferative, more estrogen responsive, Luminal-A like state by enriching ERα chromatin binding at canonical estrogen response elements. Multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) revealed kinase network reprogramming, including upregulation of PI3K and HER2 activity, as shared adaptive resistance mechanisms to vandetanib treatment. Co-treatment with the HER2 inhibitor lapatinib, further enhanced sensitivity to vandetanib. Using an operating room-to-laboratory short-term ex-vivo assay coupled to single-cell RNA sequencing, we demonstrate conserved gene expression changes in primary tumor cells, including increased HER2 activity signatures, following vandetanib treatment. Vandetanib sensitivity signatures were generated from cell line and primary human tumor cells which correlate with vandetanib sensitivity in ER+ patient-derived organoid and xenograft models. Future studies should evaluate if signatures predict responses in patients with ER+ breast tumors, and determine the role of co-targeting HER2 signaling with v...