In addition to traditional cytoplasmic signaling, the EGFR has been continually detected in the nuclei of cancer cells, primary tumor specimens and really proliferative tissues.
hts screening Increased nuclear EGFR localization correlates with poor medical outcome in patients with breast cancer, oropharyngeal SCC and ovarian cancer. Recent reports have characterized a novel nuclear localization sequence in the EGFR and its loved ones members. Moreover, mechanisms of transport of the EGFR to the nucleus have been reported. To date nuclear EGFR has been shown to regulate the promoters of several target genes such as, Cyclin Dl, iNOS, B myb, Aurora Kinase A and COX2.
Mechanisms of EGFR Paclitaxel mediated gene regulation involve direct interaction with the EGFR and STAT3 to regulate the iNOS and COX2 promoters, STAT5 for regulation of the Aurora Kinase A promoter, and E2F1 transcription variables for the regulation of the B Myb promoter. In addition, nuclear EGFR has just lately been shown to function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA and thus improving proliferative likely of cancer cells. In addition to ligand induced translocation of the EGFR to the nucleus, radiation has been shown to induce EGFR transport to the nucleus mediated by the Src family members kinases. Further, cetuximab, a monoclonal antibody targeting the EGFR, has also been proven to lead to EGFR translocation to the nucleus.
Collectively these findings propose that EGF ligand, radiation and cetuximab improve nuclear accumulation of the EGFR. Targeting the EGFR with molecular inhibitors LY364947 has been intensely pursued in the final decade as a cancer therapy method. Two main strategies have been created to target the EGFR, like anti EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors. Dating back to the early 1980s, Mendelsohn and colleagues purified a series of mAbs to the EGFR to test these agents as inhibitors of tumor growth. Born out of these efforts, cetuximab was designed to target the extracellular ligand binding domain of the EGFR and therefore block natural ligand binding. Cetuximab prevents receptor activation and dimerization and in the end induces receptor internalization and downregulation.
Cetuximab exhibits promising antitumor activity as monotherapy or in blend with chemotherapy and/or radiation in HNSCC. In a phase III clinical trial using cetuximab in locally superior HNSCC, Bonner et al. compared antigen peptide the efficacy of radiotherapy alone to radiotherapy plus cetuximab. The outcomes of this trial showed an improvement in total survival and progression totally free survival by 20 and 5 months, respectively, with the addition of cetuximab. Locoregional handle was also enhanced by a median of 9. 5 months with the addition of cetuximab to radiotherapy. The outcomes of this phase III trial demonstrating considerable improvement in locoregional manage, overall survival, and progression free of charge survival by the addition of cetuximab to radiotherapy led to the Food and Drug Administration approval of cetuximab for use in HNSCC in blend with radiation in 2006.
Numerous other trials, at various phases, more investigating the role of cetuximab have also been reported. Because the time of this report, standard study has indicated that each cetuximab and radiation can drive EGFR to the nucleus and that nuclear EGFR can outcome in resistance to Issue Xa both of these modalities. In the present research we aimed to determine if cetuximab and radiation induced EGFR translocation to the nucleus shared a frequent molecular pathway.
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