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Published on: May 30, 2012

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

Austin A Whitman1, Rasha T Kakati2, Santiago Haase2

  • 1University of North Carolina at Chapel Hill Chapel Hill United States.

Molecular Cancer Therapeutics
|July 28, 2026
PubMed

Insights

Vandetanib overcomes endocrine therapy resistance in estrogen receptor-positive breast cancer by suppressing MAPK signaling and enhancing estrogen responsiveness. Adaptive resistance mechanisms involving PI3K and HER2 signaling were identified, suggesting combination therapies may improve outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Endocrine therapy (ET) resistance is a major challenge in estrogen receptor-positive (ER+) breast cancer.
  • Upregulation of MAPK signaling pathways is a known contributor to ET resistance.

Purpose of the Study:

  • To investigate the efficacy of vandetanib in overcoming ET resistance in ER+ breast cancer.
  • To elucidate the molecular mechanisms underlying vandetanib's effects and identify adaptive resistance pathways.

Main Methods:

  • Treatment of ER+ cell lines and patient-derived organoids with vandetanib.
  • Multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) for kinase profiling.
  • Ex-vivo short-term assay with single-cell RNA sequencing on primary tumor cells.
  • Generation of vandetanib sensitivity signatures.

Main Results:

  • Vandetanib suppressed MAPK signaling and enhanced ET sensitivity in both sensitive and resistant ER+ models.
  • Vandetanib treatment shifted transcriptional profiles towards a Luminal-A-like state with increased ERα chromatin binding.
  • Adaptive resistance mechanisms involving PI3K and HER2 pathway upregulation were identified.
  • Co-treatment with lapatinib (a HER2 inhibitor) further enhanced sensitivity.
  • Vandetanib induced conserved gene expression changes in primary tumor cells, including increased HER2 activity signatures.

Conclusions:

  • Vandetanib demonstrates potential in overcoming ET resistance in ER+ breast cancer by targeting MAPK signaling and reprogramming transcription.
  • PI3K and HER2 pathway activation represent key adaptive resistance mechanisms to vandetanib.
  • Combination therapy, potentially including HER2 inhibition, warrants further investigation.
  • Vandetanib sensitivity signatures may predict treatment response in ER+ breast cancer patients.

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