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. 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-50767

Palbociclib

99.94%, CDK4/6 Inhibitor

CDK

Cancer

Name
Email *

	Sorry, but the email address you supplied was invalid.