title: Signaling mechanisms of resistance to EGFR- and Anti-Angiogenic Inhibitors cancer.
abstract: Colorectal cancer is among four most common malignancies and the second leading cause of cancer death in the western world. Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor (VEGF) are often overexpressed in colorectal cancer and are associated with inferior outcomes. More recently, further improvements in survival have occurred due to the use of novel targeted therapies such EGFR Tyrosine Kinase Inibitors (EGFR-TKIs), EGFR monoclonal antibodies (EGFR-mAb), and VEGF antibodies. Despite the initial clinical efficacy of these inhibitors in such cancer, resistance invariably develops, typically within 1 to 2 years. Over the past several years, multiple molecular mechanisms of resistance have been identified, and some common themes have emerged. One is the development of resistance mutations in the drug target and another it is activation of alternative signaling of key downstream pathways despite sustained inhibition of the original drug target. In this mini-review, we summarize the concepts underlying EGFR- and VEGF-mediated resistance, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.
authors.affiliation: Department of Medical Oncology B, Regina Elena National Cancer Institute, via Elio Chianesi 53, Rome 00144, Italy. Electronic address: gio_mirone@virgilio.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mirone
authors.affiliation: School of Biotechnology and Bioinformatics, D.Y. Patil University, Plot No.50, Sector- 15, C.B.D. Belapur, Navi Mumbai, 400614, Maharastra, India.
authors.forename: Arvind
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Biochemistry and Biophysics, Second University of Naples, via De Crecchio 7, Naples 80138, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marfe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: Colorectal cancer; Epidermal Growth Factor Receptor; Gefitinib; Vascular Endothelial Growth Factor VEGF-1