2. Academic Validation
  3. RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

  • Br J Cancer. 2021 Jan;124(1):191-206. doi: 10.1038/s41416-020-01174-z.
Derek Dustin 1 2,  Guowei Gu 1 3,  Amanda R Beyer 1,  Sarah K Herzog 1 4,  David G Edwards 1,  Hangqing Lin 1,  Thomas L Gonzalez 1,  Sandra L Grimm 3 5,  Cristian Coarfa 3 5,  Doug W Chan 1,  Beom-Jun Kim 1,  Jean-Paul De La O 6,  Matthew J Ellis 1 2 7,  Dan Liu 8,  Shunqiang Li 9,  Alana L Welm 6,  Suzanne A W Fuqua 10 11 12 13 14 15
Affiliations

Affiliations

  • 1 Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
  • 2 Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 4 Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, USA.
  • 5 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 6 University of Utah Huntsman Cancer Institute, Salt Lake City, Utah, USA.
  • 7 Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 8 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 9 Washington University School of Medicine, St. Louis, MO, USA.
  • 10 Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
  • 11 Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
  • 12 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
  • 13 Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
  • 14 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
  • 15 Department of Medicine, Baylor College of Medicine, Houston, TX, USA. sfuqua@bcm.edu.
PMID: 33257837 DOI: 10.1038/s41416-020-01174-z
Abstract

Background: Oestrogen Receptor 1 (ESR1) mutations are frequently acquired in oestrogen receptor (ER)-positive metastatic breast Cancer (MBC) patients who were treated with aromatase inhibitors (AI) in the metastatic setting. Acquired ESR1 mutations are associated with poor prognosis and there is a lack of effective therapies that selectively target these cancers.

Methods: We performed a proteomic kinome analysis in ESR1 Y537S mutant cells to identify hyperactivated kinases in ESR1 mutant cells. We validated Recepteur d'Origine Nantais (RON) and PI3K hyperactivity through phospho-immunoblot analysis, Organoid growth assays, and in an in vivo patient-derived xenograft (PDX) metastatic model.

Results: We demonstrated that RON was hyperactivated in ESR1 mutant models, and in acquired palbociclib-resistant (PalbR) models. RON and insulin-like growth factor 1 receptor (IGF-1R) interacted as shown through pharmacological and genetic inhibition and were regulated by the mutant ER as demonstrated by reduced phospho-protein expression with endocrine therapies (ET). We show that ET in combination with a RON inhibitor (RONi) decreased ex vivo Organoid growth of ESR1 mutant models, and as a monotherapy in PalbR models, demonstrating its therapeutic efficacy. Significantly, ET in combination with the RONi reduced metastasis of an ESR1 Y537S mutant PDX model.

Conclusions: Our results demonstrate that RON/PI3K pathway inhibition may be an effective treatment strategy in ESR1 mutant and PalbR MBC patients. Clinically our data predict that ET resistance mechanisms can also contribute to CDK4/6 inhibitor resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6抑制剂
    CDK
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