RON is not a prognostic marker for resectable pancreatic cancer

Tactacan, Carole M.; Chang, David K.; Cowley, Mark J.; Humphrey, Emily S.; Gill, Anthony J.; Chou, Angela; Nones, Kátia; Grimmond, Sean M.; Sutherland, Robert L.; Biankin, Andrew V.; Daly, Roger J.

doi:10.1186/1471-2407-12-395

Cited by 16 publications

(11 citation statements)

References 26 publications

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“…Moreover, aberrant RON signaling serves as a mechanism for acquired chemoresistance. However, RON expression in correlation with clinicopathophysiologic parameters has not been fully established (11). Thus, further investigation is required to demonstrate the pathogenic role of RON in PDAC malignancy.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…To the best of our knowledge, only a single study has been published: Tactacan et al (31) assessed RON expression in a total of 492 pancreatic cancer patients and evaluated the association between RON expression and patient outcomes and clinicopathological variables. The study identified that increased RON expression was a biomarker for poor prognosis in a training set.…”

Section: Discussionmentioning

confidence: 99%

A missing link between RON expression and oncological outcomes in resected left-sided pancreatic cancer

et al. 2017

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Abstract. Alteration and activation of recepteur d'origine nantais (RON) expression is known to be associated with cancer progression and decreased survival in various types of human cancer, including pancreatic cancer. Therefore, in the present study, RON expression levels were determined in resected left-sided pancreatic cancer to evaluate the potential oncological role of RON in the clinical setting of distal pancreatic cancer. From January 2005 to December 2011, a total of 57 patients underwent radical distal pancreatectomy for left-sided pancreatic cancer. Ductal adenocarcinoma was confirmed in all patients. Among these patients, 17 patients who received preoperative neoadjuvant treatment and 7 patients without available paraffin-embedded tissue blocks were excluded from the present study. RON expression in a the pancreatic cancer cell lines ASPC-1, BxPC-3, MiaPaCa-3 and Panc-1, as well as in resected left-sided pancreatic cancer specimens was determined by Western blot analysis. RON and vascular endothelial growth factor (VEGF) overexpression in resected left-sided pancreatic cancer was also evaluated by immunohistochemistry using pre-diluted anti-RON and anti-VEGF antibodies. An association was identified between the oncological outcome and RON overexpression. Increased levels of RON expression were observed in two pancreatic cancer cell lines, AsPC-1 and BxPC-3. RON overexpression was detected in specimens from 15/33 patients (45.5%) using immunohistochemistry. No significant association was identified between RON overexpression and VEGF overexpression (25.5 vs. 87.9%; P=0.667). No significant differences in disease-free survival or disease-specific survival associated with RON overexpression were identified. Although the results of previous studies have suggested that RON is a potential target for the treatment of pancreatic cancer, in the present study no association between RON overexpression and any adverse oncological effect was identified.

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“…It is well accepted that RON mediates several oncogenic functions in cancer cells, including cell proliferation and survival; cell adhesion and spreading; cell dissociation and migration; EMT and matrix invasion; and establishment of metastasis. These features point to the importance of RON in later stages of cancer and RON expression correlates strongly with invasion, tumor stage, and poor prognosis in most, but not all, cancers (Ronsin et al 1993;Wang et al 2003Wang et al , 2006Lee et al 2005;O'Toole et al 2006;Thomas et al 2007;Welm et al 2007;Catenacci et al 2011;Benight and Waltz 2012;Song et al 2012;Tactacan et al 2012).…”

Section: Signaling Pathways Downstream From Ron In Cancer Progressionmentioning

confidence: 99%

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

Faham

Welm

2016

Cold Spring Harb Symp Quant Biol

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With an increasing body of literature covering RON receptor tyrosine kinase function in different types of human cancers, it is becoming clear that RON has prominent roles in both cancer cells and in the tumor-associated microenvironment. RON not only activates several oncogenic signaling pathways in cancer cells, leading to more aggressive behavior, but also promotes an immunosuppressive, alternatively activated phenotype in macrophages and limits the antitumor immune response. These two unique functions of this oncogene, the strong correlation between RON expression and poor outcomes in cancer, and the high tolerability of a new RON inhibitor make it an exciting therapeutic target, the blocking of which offers an advantage toward improving the survival of cancer patients. Here, we discuss recent findings on the role of RON signaling in cancer progression and its potential in cancer therapy.

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RON is not a prognostic marker for resectable pancreatic cancer

Cited by 16 publications

References 26 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

A missing link between RON expression and oncological outcomes in resected left-sided pancreatic cancer

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

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