IndraLab
Statements
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"To characterize the effects of ligand binding on the conformations of the EGFR dimers, we compared structures generated during simulation runs to previously solved x-ray structures of EGFR bound to TGF-α and EGF, and the recently solved structure of another ErbB4-ligand complex xref , xref , xref ."
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"Binding of epidermal growth factor (EGF) or transforming growth factor alpha (TGF α ) to the extracellular domain of EGFR produces a number of downstream effects that affect phenotypic cell behavior including proliferation, invasion, metastasis, and inhibition of apoptosis [ xref ]."
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"Several approaches have been developed to achieve EGFR blockade as an anticancer treatment strategy, including the anti-EGFR monoclonal antibody IMC-C225, which competitively binds to the extracellular receptor site and prevents binding by the natural EGFR ligands EGF and transforming growth factor-alpha."
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"By contrast, EGF and TGF-α were also found to be a potent chemotactic factors for these thyroid carcinoma cells like HB-EGF ( xref – xref ), but these growth factors are different from HB-EGF in that EGF or TGF-α binds to HER1 alone and that HB-EGF bears a heparin binding site, which binds to cell surface heparin sulfate proteoglycan, but not EGF or TGF-α."
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"We conclude that antibodies which block the binding of EGF and transforming growth factor alpha to the EGFR can inhibit the growth of EGFR-overexpressing tumors by directing terminal differentiation and that a further therapeutic benefit may be obtained via immunological mechanisms with rat IgG2b mAbs such as ICR62."
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"Panitumumab is a fully humanized IgG2 mAb that binds with high affinity to the ligand-binding domain of EGFR. xref Panitumumab, similarly to cetuximab, competitively blocks the binding of EGF and TGFα to EGFR, thus inhibiting autophosphorylation induced by EGFR ligands. xref Cetuximab and panitumumab were recently launched and marketed for colon, head and neck, and/or lung cancers, covering a limited range of solid tumors. xref , xref Necitumumab (IMC-11F8), designed to bind and block the ligand-binding site of EGFR, is another IgG1 antibody which is currently under investigation in clinical trials of patients with NSCLC. xref , xref "
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"Neuregulin binding to these receptors is thought to promote an extension of the molecule (and exposure of the dimerization arm) similar to that seen when EGF or TGFα bind to EGFR, and this has been confirmed by X-ray scattering studies of the ErbB3 extracellular region in solution [ xref ]."
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"Zalutumumab is a fully human IgG1 mAb that targets EGFR domain III and inhibits binding of EGF and TGF-α to EGFR. xref Zalutumumab also prevents conformational changes in EGFR that are necessary for its activation. xref An open-label, randomized, Phase III trial investigated zalutumumab plus best supportive care (BSC) vs BSC alone in 286 patients with R/M HNSCC after failure of platinum-based chemotherapy. xref Zalutumumab prolonged median PFS compared with BSC alone (9.9 vs 8.4 weeks; P =0.0012)."
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"Both EGF and TGFα binding to the EGFR lead to endocytosis of EGFR, but receptor-EGF complexes are predominantly trafficked for degradation in lysosomes, while TGFα-bound receptor is predominantly recycled back to the cell surface. xref Thus, changes in ligand-dependent activation can radically impact growth factor receptor signaling."
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"It blocks the binding of EGF and transforming growth factor-alpha to EGFR and thus inhibits tumor cell growth, angiogenesis, and apoptosis. xref xref xref – xref In contrast to other approved anti-vascular endothelial growth factor agents including cetuximab and panitumumab, nimotuzumab needs bivalent binding for stable attachment to the cellular surface, leading to higher clinical efficiency and better safety. xref xref xref xref xref xref – xref Nimotuzumab has therefore been approved for the treatment of advanced head and neck cancer, nasopharyngeal cancer (NPC), glioma, and esophageal cancer in 30 countries. xref xref xref xref xref xref – xref In China, nimotuzumab was approved as a drug in combination with radiotherapy for the treatment of NPC in 2008 and was recommended by the Chinese edition of the National Comprehensive Cancer Network (NCCN) guidelines as a targeted therapy for NPC in 2009. xref "
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"Residues S418 and G471, while not predicted to affect the interaction of EGFR with endogenous ligands EGF and TGF-α, may be important for interaction with one or more of the remaining five endogenous ligands such that mutation at these residues reduces clonal fitness and persistence."