The anti-EGFR monoclonal antibodies, cetuximab and panitumumab, are effective in a subset of colorectal cancer patients. However, acquisition of resistance to these drugs invariably develops. Elucidation of the molecular mechanisms underlying resistance is a crucial first step to develop therapeutic strategies to bypass secondary resistance. Three mechanisms of resistance have been characterized in patients so far: a mutation in the extracellular domain of EGFR preventing cetuximab-EGFR binding - interestingly, this mutation does not affect panitumumab effectiveness; activation of EGFR-related receptor HER2 by amplification or ligand overexpression; emergence of KRAS mutations or amplification.lmportantly,alreadyapproveddrugscan be used to bypass known mechanisms of resistance. Large-scale studies including biopsy at progression and prospective clinical trials are warranted.
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