Epidermal growth factor receptor inhibitors in colorectal cancer: it's time to get back on target.

摘要: A key signature of targeted cancer therapy is selectivity. This selectivity depends on identification a target that tightly associated with the malignant phenotype. Inhibition must alter this phenotype and not adversely affect normal tissues. An ability to measure presence requirement for clinical development, such individuals tumors do express are spared exposure ineffective treatment. Inhibitors epidermal growth factor receptor (EGFR) illustrate some triumphs pitfalls development therapy. Murine was identified more than 40 years ago, its human homolog were isolated 15 later. 1-5 Subsequently, shown have intrinsic kinase activity. 5 During 1980s 1990s, several significant observations established EGFR as potential therapeutic target. 6,7 First, studies demonstrated homology between proto-oncogene v-erbB. 8 Second, frequent expression found in variety epithelial malignancies, conferring poor prognosis. Finally, inhibitory antibodies small molecules block phosphorylation, cellular proliferation, xenograft growth. 9-12 Given colorectal (approximately 70% 75% by immunohistochemistry [IHC]), 13 malignancy appropriate inhibitors. Clinical activity has been anti-EGFR monoclonal cetuximab 14-16 (a human-mouse chimera) panitumumab 17 fully antibody) patients metastatic cancer. Cetuximab approved US Food Drug Administration use EGFRexpressing 18 Based models indicated potentiation cytotoxic chemotherapy, 11 initial phase II trial combination study irinotecan plus cetuximab. 14 Subsequent trials confirmed hypothesis superior monotherapy, response rates approximately 20%v 10%, respectively, who previously showed resistance irinotecan. 15,16 The most common toxicity skin rash, severity rash consistently predictive survival 14,16 observation led exploration surrogate pharmacodynamic marker inhibition, numerous predicted downstream perturbations signaling, phosphorylated EGFR, AKT, Ki67, p27 treated antibody small-molecule 19-21 Unfortunately, clear association signaling inhibition antitumor found.