Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase

Liu, Xuemei; Zhao, Ling; DeRose, Yoko S.; Lin, Yi Chun; Bieniasz, Magdalena; Eyob, Henok; Buys, Saundra S.; Neumayer, Leigh; Welm, Alana L.

doi:10.1177/1947601911421924

Cited by 40 publications

(86 citation statements)

References 34 publications

(60 reference statements)

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“…Inhibition of RON has implicated its signaling for PDAC cell growth and survival in preclinical studies (2)(3)(4)(5)(6)10). Various studies have shown that therapeutic antibodies and TKIs specific to RON inhibit tumor growth mediated by pancreatic, colon, and breast cancer cells in mouse tumor xenograft models (7,12,13,31).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that RON is overexpressed and activated in primary PDAC samples and established cell lines (1)(2)(3)(4)(5)(6). Here, we determined the therapeutic effect of BMS-777607 on RON signaling in L3.6pl cells and CSCs þ24/44/ESA .…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of the recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) in cancer cells has been implicated in tumorigenic activities and malignant progression (1)(2)(3)(4). Aberrant RON expression also has been molecularly targeted in mouse xenograph models of pancreatic ductal adenocarcinoma (PDAC; refs.…”

Section: Introductionmentioning

confidence: 99%

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Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Zeng

Sharma

Zhou

et al. 2014

Molecular Cancer Therapeutics

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Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of BMS-777607 in combination with mTOR inhibitor AZD8055 in killing chemoresistant pancreatic cancer and cancer stem cells. Treatment of pancreatic cancer L3.6pl cells with BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However, BMS-777607 caused extensive polyploidy in L3.6pl cells through inhibition of aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of BMS-777607 on induction of cancer stem cell polyploidy was also weak. BMS-777607-induced polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC 50 values in response to doxorubicin, cisplatin, methotrexate, 5-fluorouracial, and gemcitabine. Among a panel of chemical inhibitors that target different signaling proteins, we found that BMS-777607 in combination with mTOR inhibitor AZD8055 exerted synergistic effects on L3.6pl and cancer stem cells. More than 70% of L3.6pl and cancer stem cells lost their viability when both inhibitors were used. Specifically, BMS-777607 in combination with inhibition of mTORC2, but not mTORC1, was responsible for the observed synergism. Our findings demonstrate that BMS-777607 at therapeutic doses exerts inhibitory activities on pancreatic cancer cells but also induces polyploidy insensitive to chemotherapeutics. Combination of BMS-777607 with AZD8055 achieves the maximal cytotoxic effect on pancreatic cancer and cancer stem cells. Mol Cancer Ther; 13(1); 37-48. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Zeng

Sharma

Zhou

et al. 2014

Molecular Cancer Therapeutics

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“…In tumor cells, overexpression of RON results in proliferation, migration, and a more aggressive phenotype. 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.…”

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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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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“…We recently discovered that an alternative isoform of Ron, known as short-form Ron (sfRon), is also a significant contributor to breast cancer pathogenesis (4). sfRon is generated by alternative transcription from a second promoter within exon 10 of the RON gene (5).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts

Bieniasz

Radhakrishnan

Faham

et al. 2015

Clinical Cancer Research

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Purpose Recent studies have demonstrated that short-form Ron (sfRon) kinase drives breast tumor progression and metastasis through robust activation of the PI3K pathway. We reasoned that upfront, concurrent inhibition of sfRon and PI3K might enhance the anti-tumor effects of Ron kinase inhibitor therapy while also preventing potential therapeutic resistance to tyrosine kinase inhibitors (TKIs). Experimental design We used patient-derived breast tumor xenografts (PDXs) as high-fidelity pre-clinical models to determine the efficacy of single agent or dual Ron/PI3K inhibition. We tested the Ron kinase inhibitor ASLAN002 with and without co-administration of the PI3K inhibitor NVP-BKM120 in hormone receptor positive (ER+/PR+) breast PDXs with and without PIK3CA gene mutation. Results Breast PDX tumors harboring wild-type PIK3CA showed a robust response to ASLAN002 as a single agent. In contrast, PDX tumors harboring mutated PIK3CA demonstrated partial resistance to ASLAN002, which was overcome with addition of NVP-BKM120 to the treatment regimen. We further demonstrated that concurrent inhibition of sfRon and PI3K in breast PDX tumors with wild-type PIK3CA provided durable tumor stasis after therapy cessation, whereas discontinuation of either monotherapy facilitated tumor recurrence. Conclusion Our work provides pre-clinical rationale for targeting sfRon in breast cancer patients, with the important stipulation that tumors harboring PIK3CA mutations may be partially resistant to Ron inhibitor therapy. Our data also indicate that tumors with wild type PIK3CA are most effectively treated with an upfront combination of Ron and PI3K inhibitors for the most durable response.

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Short-Form Ron Promotes Spontaneous Breast Cancer Metastasis through Interaction with Phosphoinositide 3-Kinase

Cited by 40 publications

References 34 publications

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

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

Preclinical Efficacy of Ron Kinase Inhibitors Alone and in Combination with PI3K Inhibitors for Treatment of sfRon-Expressing Breast Cancer Patient-Derived Xenografts

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