title: Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer.
abstract: Administration of monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer (mCRC). However, the efficacy of these mAbs is limited due to genetic variation among patients, in particular K-ras mutations. The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC. Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF, MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors. Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation, our understanding of their mode of action is limited. Rational drug development based on stringent preclinical data, biomarker validation, and proper selection of patients is of paramount importance in the treatment of mCRC. In this review, we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFR-Ras-ERK and PI3K signalings.
authors.affiliation: Woo-Jeong Jeong, Pu-Hyeon Cha, Kang-Yell Choi, Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Woo-Jeong
authors.initials: WJ
authors.lastname: Jeong
authors.affiliation: Woo-Jeong Jeong, Pu-Hyeon Cha, Kang-Yell Choi, Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Pu-Hyeon
authors.initials: PH
authors.lastname: Cha
authors.affiliation: Woo-Jeong Jeong, Pu-Hyeon Cha, Kang-Yell Choi, Translational Research Center for Protein Function Control, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea.
authors.forename: Kang-Yell
authors.initials: KY
authors.lastname: Choi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Colorectal cancer; Combinational therapy; Epidermal growth factor receptor; K-ras mutation; Resistance
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