Résultats de recherche pour « EGFR »

The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as 'noncanonical') functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand-induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress-induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.

BACKGROUND: Recent clinical trials suggest that epidermal growth factor receptor (EGFR)-targeted agents could benefit many patients with cancer. METHODS: We review the current status of several EGFR-targeted therapies in cancer patients and address the efficacy of theses drugs as monotherapy or in combination with other drugs and/or treatments. RESULTS: Cetuximab is the most widely studied anti-EGFR monoclonal antibody. Other monoclonal antibody agents under investigation are panitumumab, matuzumab, MDX-447, nimutozumab, and mAb806. Extensive research has also evaluated the efficacy of EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib, EKB-569, lapatinib (GW572016), PKI-166, and canertinib (CI-1033). All of these agents have been studied for the treatment of colorectal, lung, breast, pancreatic, renal, head and neck, gynecologic, and prostate cancer. Currently, cetuximab and panitumumab are FDA approved for the treatment of metastatic colorectal cancer. Additionally, cetuximab is approved for head and neck cancer. Erlotinib is FDA approved for advanced/metastatic lung cancer. Erlotinib in combination with gemcitabine is approved for advanced/metastatic pancreatic cancer treatment. CONCLUSIONS: EGFR-targeted agents have already shown utility in different scenarios. Researchers are continuously investigating additional cancer types and combined treatment modalities that could also benefit from the use of EGFR-targeted agents. Careful patient selection through the identification of specific biologic markers, such as gene expression, genomic polymorphism, and posttranslational modifications of EGFR downstream effectors, most likely will contribute to the successful use of these agents.

Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.

Epidermal growth factor receptor (EGFR) is the first discovered member of the receptor tyrosine kinase superfamily and plays a fundamental role during embryogenesis and in adult tissues, being involved in growth, differentiation, maintenance and repair of various tissues and organs. The role of EGFR in the regulation of tissue development and homeostasis has been thoroughly investigated and it has also been demonstrated that EGFR is a driver of tumorigenesis. In the nervous system, other growth factors, and thus other receptors, are important for growth, differentiation and repair of the tissue, namely neurotrophins and neurotrophins receptors. For this reason, for a long time, the role of EGFR in the nervous system has been underestimated and poorly investigated. However, EGFR is expressed both in the central and peripheral nervous systems and it has been demonstrated to have specific important neurotrophic functions, in particular in the central nervous system. This review discusses the role of EGFR in regulating differentiation and functions of neurons and neuroglia. Furthermore, its involvement in regeneration after injury and in the onset of neurodegenerative diseases is examined.