Impact of genomic heterogeneity associated with acquired anti-EGFR resistance in colorectal cancers.

Abstract

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies approved by the Food and Drug Administration of the Unites States for treatment of patients with metastatic colorectal cancers, but the response rate is only around 10% in unselected patient populations (1). Despite initial response to cetuximab and panitumumab, almost all patients develop resistance within several months of anti-EGFR-therapy. Mechanisms for acquired resistance to targeted therapeutics with small molecule kinase inhibitors have been extensively studied, because new inhibitors can be designed to overcome the resistance mutations which commonly happen in the kinase domain of the targeted kinase (2). For example, the most common resistance mutation, EGFR p.T790M, is detected in 50–60% or more of lung cancer patients who progressed during treatment with first-generation or second-generation EGFR tyrosine kinase inhibitors (3). Detection of p.T790M has become a common clinical practice to select patients with non-small cell lung cancers for third-generation tyrosine kinase inhibitors.