Related Experiment Video

Updated: Aug 2, 2025

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

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Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer

Xuxu Gou1,2,3, Beom-Jun Kim1,4, Meenakshi Anurag1,4

  • 1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.

Cancer Research
|April 18, 2023
PubMed

Insights

Targeting RET kinase offers a new treatment strategy for endocrine therapy-resistant breast cancer. This approach addresses resistance caused by estrogen receptor 1 (ESR1) fusions by inhibiting upregulated RET kinase.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Transcriptionally active ESR1 fusions (ESR1-TAFs) drive endocrine therapy (ET) resistance in breast cancer.
  • ESR1-TAFs are inherently undruggable due to altered C-terminal domains, necessitating alternative therapeutic strategies.

Purpose of the Study:

  • To identify druggable kinases upregulated by ESR1-TAFs.
  • To evaluate RET kinase as a potential therapeutic target for ESR1-TAF-driven breast cancer.

Main Methods:

  • Utilized mass spectrometry-based kinase inhibitor pulldown assay (KIPA) to screen for kinases associated with ESR1-TAFs.
  • Conducted drug sensitivity studies using organoids and xenografts from patient-derived models.

Main Results:

  • Identified RET kinase as a common vulnerability across diverse ESR1-TAFs.
  • Demonstrated that the selective RET inhibitor pralsetinib effectively inhibited tumor growth in preclinical models, comparable to CDK4/6 inhibitors.

Conclusions:

  • RET kinase inhibition presents a promising therapeutic avenue for patients with ESR1-TAF-driven endocrine therapy-resistant breast cancer.
  • These findings support the clinical investigation of RET inhibitors for this patient population.

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