Epithelial Membrane Protein-1 as a Biomarker of Gefitinib Resistance
Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on epithelial growth factor receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. Epithelial membrane protein-1 (EMP-1), an adhesion molecule, has been identified as a surface biomarker whose expression correlates with acquisition of gefitinib resistance. EMP-1 expression further correlates with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance is independent of gefitinib-sensitizing EGFR somatic mutations. There is a probable cross-talk between this molecule and the EGFR signaling pathway.