Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification

Tanizaki, Junko; Okamoto, Isamu; Sakai, Kazuko; Nakagawa, Kazuhiko

doi:10.1038/bjc.2011.322

Cited by 106 publications

(99 citation statements)

References 24 publications

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“…An RTK can induce activation of structurally unrelated RTKs, for instance, stimulation of IGF-1R can lead to EGFR (Ahmad et al 2004) or ErbB2 activity (Balana et al 2001). At least two mechanisms of cross talk were suggested: direct dimerization between structurally independent RTKs, such as IGF-1R or c-Met with ErbB family receptors (Balana et al 2001;Ahmad et al 2004;Tanizaki et al 2011) and transactivation mediated by a cytoplasmic tyrosine kinase, such as Src. In the latter case, once activated by IGF-1R, Src binds and phosphorylates EGFR, thus promoting EGFR catalytic activity (Jones et al 2006).…”

Section: Rtk Pathway Cross Talk: Fine Balances At Multiple Levelsmentioning

confidence: 99%

Complexity of Receptor Tyrosine Kinase Signal Processing

Volinsky

Kholodenko

2013

Cold Spring Harbor Perspectives in Biology

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Our knowledge of molecular mechanisms of receptor tyrosine kinase (RTK) signaling advances with ever-increasing pace. Yet our understanding of how the spatiotemporal dynamics of RTK signaling control specific cellular outcomes has lagged behind. Systems-centered experimental and computational approaches can help reveal how overlapping networks of signal transducers downstream of RTKs orchestrate specific cell-fate decisions. We discuss how RTK network regulatory structures, which involve the immediate posttranslational and delayed transcriptional controls by multiple feed forward and feedback loops together with pathway cross talk, adapt cells to the combinatorial variety of external cues and conditions. This intricate network circuitry endows cells with emerging capabilities for RTK signal processing and decoding. We illustrate how mathematical modeling facilitates our understanding of RTK network behaviors by unraveling specific systems properties, including bistability, oscillations, excitable responses, and generation of intricate landscapes of signaling activities.

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Section: Rtk Pathway Cross Talk: Fine Balances At Multiple Levelsmentioning

confidence: 99%

Complexity of Receptor Tyrosine Kinase Signal Processing

Volinsky

Kholodenko

2013

Cold Spring Harbor Perspectives in Biology

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“…SH2B1 β through the SH2 domain binds to RET isoforms and its oncogenic derivatives to protect RET from dephosphorylation by protein tyrosine phosphatases, and perhaps represent a likely mechanism contributing to its upregulation that is a crucial initiating event in thyroid cancers (Donatello et al, 2007). Excessive activation of RET also has been observed in lung cancer (Tanizaki et al, 2011;Ju et al, 2012). RET is reported to activate diverse intracellular signaling cascades that regulate cellular chemotaxis, branching morphogenesis, synaptic plasticity, survival, proliferation and migration, SH2B1 β adaptor protein perhaps takes part in the lung cancer's progression as a key enhancer of RET physiologic and pathologic activities.…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance of SH2B1 Adaptor Protein Expression in Non-small Cell Lung Cancer

Zhang

Duan²,

Chen³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The SH2B1 adaptor protein is recruited to multiple ligand-activated receptor tyrosine kinases that play important role in the physiologic and pathologic features of many cancers. The purpose of this study was to assess SH2B1 expression and to explore its contribution to the non-small cell lung cancer (NSCLC). Methods: SH2B1 expression in 114 primary NSCLC tissue specimens was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients' outcome. Additionally, 15 paired NSCLC background tissues, 5 NSCLC cell lines and a normal HBE cell line were evaluated for SH2B1 expression by RT-PCR and immunoblotting, immunofluorescence being applied for the cell lines. Results: SH2B1 was found to be overexpressed in NSCLC tissues and NSCLC cell lines. More importantly, high SH2B1 expression was significantly associated with tumor grade, tumor size, clinical stage, lymph node metastasis, and recurrence respectively. Survival analysis demonstrated that patients with high SH2B1 expression had both poorer diseasefree survival and overall survival than other patients. Multivariate Cox regression analysis revealed that SH2B1 overexpression was an independent prognostic factor for patients with NSCLC. Conclusions: Our findings suggest that the SH2B1 protein may contribute to the malignant progression of NSCLC and could offer a novel prognostic indicator for patients with NSCLC.

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“…As such, the MET signaling pathway has been recognized as an attractive target in RCC (4). In addition, heterodimerization with other RTKs, including EGFR, HER2, HER3, and RET, has been proposed as a means to activate MET signaling in cancer (5).…”

Section: Introductionmentioning

confidence: 99%

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

Schuller

Barry

Jones

et al. 2015

Clinical Cancer Research

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Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a doseand time-dependent induction of cleaved PARP, a marker of cell death.Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

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Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification

Cited by 106 publications

References 24 publications

Complexity of Receptor Tyrosine Kinase Signal Processing

Complexity of Receptor Tyrosine Kinase Signal Processing

Clinical Significance of SH2B1 Adaptor Protein Expression in Non-small Cell Lung Cancer

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

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