Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

Abstract

The epidermal growth factor receptor (eGFR) is a receptor tyrosine kinase belonging to the HeR family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the Pi3K/AKT, RAs/RAF/MeK/ eRK and PLCγ/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. increased activation by gene amplification, protein overexpression or mutations of the eGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NsCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the eGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five eGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKis) and two monoclonal antibodies have gained FdA approval for use in oncology. Both approaches to targeting the eGFR have shown clinical promise and the anti-eGFR antibody cetuximab is used to treat HNsCC and CRC. despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. in this review we focus on the biology of the eGFR, the role of eGFR in human cancer, the development of

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

“…In the present study, we confirmed the high expression of PXN and that SW480 cells were not sensitive to cetuximab. The main reason for the resistance to cetuximab may be that the signaling pathway in the downstream of KRAS was not blocked although EGFR was inhibited by cetuximab treatment (19,20). The high expression of PXN may also be one of the reasons.…”

Efficacy and Safety of Endostar®Combined with Chemotherapy in Patients with Advanced Soft Tissue Sarcomas

“…There are some examples of drugs targeting neoplasm. Some EGFR inhibitors, including small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies such as erlotinib, crizotinib, gefitinib, cetuximab and bevacizumab have been approved by the U.S. Food and Drug Administration (FDA), and many of them have already been recommended by the National Comprehensive Cancer Network (NCCN) as the first or second line systemic therapy for NSCLC patients (Cohen et al, 2010;Sasaki et al, 2011;Brand et al, 2011). Now, many new drugs are available for cancers, such as bevacizumab for vascular endothelial growth factor (VEGF) in colorectal cancer, trastuzumab for her2/neu over-expressing metastatic breast cancer, cetuximab for EGFR over-expressing metastatic colorectal cancer, imatinib for bcr/abl-positive chronic myelogenous leukemia, and rituximab for non-Hodgkin's lymphoma, gemtuzumab for acute myelogenous leukemia, alemtuzumab for chronic lymphocytic leukemia, and bortezomib for proteasome in multiple myeloma.…”

Characterization of the expression and clinical features of epidermal growth factor receptor and vascular endothelial growth factor receptor-2 in esophageal carcinoma

“…Domestic (Chinese) and foreign studies have identified an overexpression of EGFR protein in esophageal carcinoma (7,8). This phenomenon is correlated with tumor cell proliferation, invasion, metastasis, vascular growth and inhibition of cell apoptosis, and is associated with poor prognosis (7,9). Reports of the expression rate of EGFR in esophageal cancer tissues are vary significantly, ranging from 29 to 99% (10,11).…”