RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer

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.

Assessment of durable chemoimmunotherapy response via circulating tumor DNA in advanced esophageal squamous cell carcinoma

“…Plasma sample at disease progression of one patient with baseline TMB‐H revealed two acquired mutations, MST1R and MLL3 . According to previous studies, colorectal patients with MLL3 mutation could benefit from ICI therapy, while MST1R signaling promoted therapeutic resistance in ESR1 mutant breast cancer 17,18 . Apart from mutations, the tumor immune microenvironment in ESCC, such as PD‐L1 expression on tumors and tumor‐infiltrating lymphocytes, may also potentially influence the patient's response to ICIs and should be further investigated 19 …”

An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer

“…Specifically, TAMs, myeloid-derived suppressor cells and dendritic cells have been shown to play a crucial role in tumor immune evasion by secreting IL-10, IL-12 and arginase-1, leading to suppression of CD8+ T-cell activity and reduced activity of effector T cells [ 63 , 64 ]. Interestingly, the receptor tyrosine kinase RON, which is expressed on resident macrophages, has been recently shown to promote endocrine therapy resistance in ESR1 mutated breast cancers [ 65 ]. Thus, since most of the tumor-infiltrating cells are of myeloid origin, our immune-humanized model would be an interesting system to study this mechanism further.…”

Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

“…As discussed above, ESR1 mutations contribute to therapy resistance and metastasis in ER+ breast cancers. PDX models bearing naturally occurring ESR1 mutations have been valuable tools with which to test endocrine therapies (5) and targeted inhibitors against oncogenic kinases such as RON to overcome endocrine therapy resistance (139). Furthermore, use of PDX models affords the capacity to test the efficacy of stromatargeted therapies such as anti-angiogenesis agents (140) and endothelium-targeted chimeric antigen receptor T cells (141).…”