RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

Faham, Najme; Welm, Alana L.

doi:10.1101/sqb.2016.81.031377

Cited by 21 publications

(25 citation statements)

References 155 publications

(237 reference statements)

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“…Short-term treatment of the macrophages with inhibitors of transcription or translation (actinomycin D or cycloheximide, respectively) prior to MSP stimulation completely abrogated MSP-mediated upregulation of CD80 and PD-L1 (Figure 2a). Since RON can signal through both MAPK and PI3K pathways to control gene expression, 26,31 we tested the activity of, and the requirement for, these two signaling nodes in the regulation of CD80 and PD-L1. Western blot analysis of MSP-treated macrophages revealed phosphorylated forms of ERK and AKT as surrogates of MAPK and PI3K pathway activation, respectively (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

“…25–28 Particularly, overexpression of RON in breast tumors is associated with increased metastasis and poor clinical outcomes. 16,26 In macrophages, activation of RON by MSP results in attenuation of immune responses. 29–33 Previously, we and others have shown that host RON signaling negatively regulates antitumor immunity in mouse models of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…RON activation in cancer can occur through MSP-mediated stimulation of the receptor and/or by overexpression of the receptor independent of its ligand. 4 , 17 In order to examine both ligand-dependent and ligand-independent RON activation, we engineered human estrogen receptor positive breast cancer cells (T47D cells) to conditionally overexpress RON upon addition of doxycycline. This strategy enabled us to titer the expression level of RON by increasing the concentration of doxycycline.…”

Section: Resultsmentioning

confidence: 99%

“…Although they are less commonly expressed than full-length RON, alternative isoforms of RON have also been shown to mediate activation of different signaling pathways in several epithelial cancers. 17 An example of a constitutively active variant of RON is short-form RON (sfRON). We have previously shown that overexpression of sfRON in nonmetastatic MCF7 breast cancer cells was sufficient to convert them into fast-growing, metastatic tumors.…”

Section: Introductionmentioning

confidence: 99%

mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential

2018

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Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6. Further analysis revealed that RON strongly signals through mTORC1/p70S6K, which is mediated predominantly by the PI3K pathway. A targeted mutation approach to modulate RON signaling validated the importance of PI3K/mTORC1 pathway for spontaneous metastasis in vivo. Finally, inhibition of mTORC1 with an FDA-approved drug, everolimus, resulted in transient shrinkage of established RON-dependent metastases, and combined blockade of mTORC1 and RON delayed progression. These studies have identified a key downstream mediator of RON-dependent metastasis in breast cancer cells and revealed that inhibition of mTORC1, or combined inhibition of mTORC1 and RON, may be effective for treatment of metastatic breast cancers with elevated expression of RON.

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“… 10 11 12 13 14 15 16 17 At least nine types of RON isoforms have been identified: RONΔ170, RONΔ165, RONΔ165.e11p, RONΔ160, RONE5/6in, RONΔ155, RONΔp110, RONΔ85 and RONΔ55. 18 19 …”

Section: What Is Ron?mentioning

confidence: 99%

Role of Recepteur D'origine Nantais on Gastric Cancer Development and Progression

et al. 2017

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Recepteur d'origine nantais (RON) is a receptor tyrosine kinase belonging to the subfamily of which c-MET is the prototype. Large epidemiologic studies have confirmed the strong association between RON and gastric cancer development. Constitutive activation of RON signaling directly correlates with tumorigenic phenotypes of gastric cancer and a poor survival rate in advanced gastric cancer patients. In this review, we focus on recent evidence of the aberrant expression and activation of RON in gastric cancer tumors and provide insights into the mechanism of RON signaling associated with gastric cancer progression and metastasis. Current therapeutics against RON in gastric cancer are summarized.

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RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers

Cited by 21 publications

References 155 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential

Role of Recepteur D'origine Nantais on Gastric Cancer Development and Progression

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