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
  • 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. [email protected].
  • 11. Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 12. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 13. Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 14. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 15. Department of Medicine, Baylor College of Medicine, Houston, TX, USA. [email protected].
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.

Products