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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

10.8K

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

Derek Dustin1,2, Guowei Gu1,3, Amanda R Beyer1

  • 1Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.

British Journal of Cancer
|December 1, 2020
PubMed
Abstract

Insights

Targeting the RON/PI3K pathway with inhibitors shows promise for treating estrogen receptor (ER)-positive metastatic breast cancer (MBC) with ESR1 mutations. Combination therapy effectively reduced tumor growth and metastasis in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Estrogen Receptor 1 (ESR1) mutations are common in ER-positive metastatic breast cancer (MBC) following aromatase inhibitor (AI) treatment.
  • These mutations confer poor prognosis and lack targeted therapies.
  • Understanding resistance mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To identify hyperactivated kinases in ESR1 mutant cells using proteomic kinome analysis.
  • To investigate the therapeutic potential of targeting identified pathways in ESR1-mutant and resistant breast cancer models.

Main Methods:

  • Proteomic kinome analysis of ESR1 Y537S mutant cells.
  • Validation of kinase hyperactivity using phospho-immunoblotting and organoid assays.
  • In vivo studies using patient-derived xenograft (PDX) metastatic models.

Main Results:

  • Receptor D'Origine Nantais (RON) and PI3K pathways were found to be hyperactivated in ESR1 mutant and palbociclib-resistant (PalbR) models.
  • RON and insulin-like growth factor 1 receptor (IGF-1R) interaction was confirmed, regulated by mutant ER.
  • Combination therapy with endocrine therapy (ET) and a RON inhibitor (RONi) reduced organoid growth and metastasis in preclinical models.

Conclusions:

  • RON/PI3K pathway inhibition represents a potential therapeutic strategy for ESR1-mutant and PalbR MBC.
  • Endocrine therapy resistance mechanisms may also contribute to CDK4/6 inhibitor resistance.
  • Targeting RON offers a novel approach for overcoming treatment resistance in metastatic breast cancer.

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