Ron receptor tyrosine kinase signaling as a therapeutic target

Benight, Nancy M.; Waltz, Susan E.

doi:10.1517/14728222.2012.710200

Cited by 31 publications

(28 citation statements)

References 87 publications

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“…Preclinical studies have shown that RON is overexpressed and activated in breast cancer cells, which facilitates malignant tumor progression (13). Here, we determined the therapeutic effect of BMS-777607 on RON-mediated signaling in breast cancer cells.…”

Section: Discussionmentioning

confidence: 96%

“…In colon and breast cancer cells, knockdown of RON expression by specific siRNA significantly attenuates tumor cell growth and increases apoptotic cell death (10)(11)(12). These observations provide the rationale for targeting RON as a potential cancer therapy (13,14). At present, inhibition of RON by therapeutic monoclonal antibodies (mAb) and small-molecule inhibitors (SMI) has been studied in preclinical models (10,(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

Sharma

Zeng

Zhuang

et al. 2013

Molecular Cancer Therapeutics

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The RON receptor tyrosine kinase is a therapeutic target for cancer treatment. Here, we report therapeutic effect and phenotypic change of breast cancer cells in response to BMS-777607, a RON tyrosine kinase inhibitor. Treatment of breast cancer cells with BMS-777607 at therapeutic doses inhibited cancerous clonogenic growth but had only minimal effect on cell apoptosis. Significantly, BMS-777607 induced extensive polyploidy with multiple sets of chromosomes in cancer cells. This effect is independent of RON expression. Knockdown of RON in T-47D and ZR-75-1 cells by specific siRNA did not prevent polyploid formation. Immunofluorescent analysis of a-tubulin and g-tubulin expression in polyploid cells revealed that BMS-777607 disrupts bipolar spindle formation and causes multipolar-like microtubule assembly. Also, both metaphase equatorial alignment and chromosomal segregation were absent in polyploid cells. These results suggest that cellular mitosis arrests at prophase/pro-metaphase and fails to undergo cytokinesis. By analyzing kinase-inhibitory profiles, aurora kinase B was identified as the target molecule inhibited by BMS-777607. In BMS-777607-treated cells, aurora kinase B was inhibited followed by protein degradation. Moreover, BMS-777607 inhibited Ser10 phosphorylation of histone H3, a substrate of aurora kinase B. Chemosensitivity analysis indicated the resistance of polyploid cells toward chemotherapeutics. Treatment with doxorubicin, bleomycin, methotrexate, and paclitaxel significantly increased cellular IC 50 values. These findings highlight the theory that BMS-777607 acts as a multikinase inhibitor at therapeutic doses and is capable of inducing polyploidy by inhibiting aurora kinase B. Increased resistance of polyploid cells to cytotoxic chemotherapeutics could have a negative impact on targeted cancer therapy using BMS-777607. Mol Cancer Ther; 12(5); 725-36. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

Sharma

Zeng

Zhuang

et al. 2013

Molecular Cancer Therapeutics

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“…4 and Supplementary Fig. 8), we tested our phage approach against pro-macrophage stimulating protein (pro-MSP), another plasminogen-related growth factor also known as hepatocyte growth factor-like 41,42 . Similar to pro-HGF, extracellular pro-MSP resides in an inactive zymogenlike form until proteolytic cleavage activates the serine protease-like β-chain for binding and subsequent signaling through its receptor, RON.…”

Section: Zaptide Specificity and Activation Of A Protease Zymogenmentioning

confidence: 99%

“…Similar to pro-HGF, extracellular pro-MSP resides in an inactive zymogenlike form until proteolytic cleavage activates the serine protease-like β-chain for binding and subsequent signaling through its receptor, RON. The MSP-RON signaling pathway promotes wound healing and suppresses the pro-inflammatory immune response but is also implicated in invasive tumor growth 41,42 . Using a new cyclic library based on ZAP2.3 (Supplementary Table 5) and TrAPT sorting, we discovered ZAP3.2, a ZAPtide specific for activating the zymogenlike pro-MSP β-chain (zMSP β) to bind RON with an EC 50 of 134 μM ( Fig.…”

Section: Zaptide Specificity and Activation Of A Protease Zymogenmentioning

confidence: 99%

An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides

Landgraf¹,

Steffek

Quan³

et al. 2014

Nat Chem Biol

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Stimulation of hepatocyte growth factor (HGF) signaling through the Met receptor is an attractive approach for promoting tissue repair and preventing fibrosis. Using structure-guided peptide phage display combined with an activity-based sorting strategy, we engineered allosteric activators of zymogen-like pro-HGF to bypass proteolytic activation and reversibly stimulate pro-HGF signaling through Met. Biochemical, structural and biological data showed that zymogen activator peptides (ZAPtides) potently and selectively bind the activation pocket within the serine protease-like β-chain of pro-HGF and display titratable activation of pro-HGF-dependent Met signaling, leading to cell survival and migration. To further demonstrate the versatility of our ZAPtide platform, we identified allosteric activators for pro-macrophage stimulating protein and a zymogen serine protease, Protein C, which also provides evidence for target selectivity. These studies reveal that ZAPtides use molecular mimicry of the trypsin-like N-terminal insertion mechanism and establish a new paradigm for selective pharmacological activation of plasminogen-related growth factors and zymogen serine proteases.

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“…The receptor tyrosine kinases (RTKs) RON (also known as macrophage stimulating 1 receptor MST1R) and MET form a two-member family of so-called scatter factor receptors, based on closely related structure and function [1]. While MET signaling is a well-recognized oncogenic pathway in many cancers, first findings assigned RON a role in the regulation of innate immunity, limiting macrophage motility and inflammatory response [2,3]. Further studies demonstrated an expression in various tumors, linking RON to tumorigenesis and progression as well [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

The Receptor Tyrosine Kinase RON and Its Isoforms as Therapeutic Targets in Ewing Sarcoma

Berning

Hennemann

Tulotta

et al. 2020

Cancers

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The receptor tyrosine kinase (RTK) RON is linked to an aggressive metastatic phenotype of carcinomas. While gaining interest as a therapeutic target, RON remains unstudied in sarcomas. In Ewing sarcoma, we identified RON among RTKs conferring resistance to insulin-like growth factor-1 receptor (IGF1R) targeting. Therefore, we explored RON in pediatric sarcoma cell lines and an embryonic Tg(kdrl:mCherry) zebrafish model, using an shRNA-based approach. To examine RON-IGF1R crosstalk, we employed the clinical-grade monoclonal antibody IMC-RON8, alone and together with the IGF1R-antibody IMC-A12. RON silencing demonstrated functions in vitro and in vivo, particularly within micrometastatic cellular capacities. Signaling studies revealed a unidirectional IGF1-mediated cross-activation of RON. Yet, IMC-A12 failed to sensitize cells to IMC-RON8, suggesting additional mechanisms of RON activation. Here, RT-PCR revealed that childhood sarcomas express short-form RON, an isoform resistant to antibody-mediated targeting. Interestingly, in contrast to carcinomas, treatment with DNA methyltransferase inhibitor did not diminish but increased short-form RON expression. Thus, this first report supports a role for RON in the metastatic progression of Ewing sarcoma. While principal molecular functions appear transferrable between carcinomas, Ewing sarcoma and possibly more common sarcoma subtypes, RON highlights that specific regulations of cellular networks and isoforms require better understanding to successfully transfer targeting strategies.

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Ron receptor tyrosine kinase signaling as a therapeutic target

Cited by 31 publications

References 87 publications

Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

Small-Molecule Inhibitor BMS-777607 Induces Breast Cancer Cell Polyploidy with Increased Resistance to Cytotoxic Chemotherapy Agents

An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides

The Receptor Tyrosine Kinase RON and Its Isoforms as Therapeutic Targets in Ewing Sarcoma

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