PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab

摘要: Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown lack of association between EGFR overexpression and cetuximab response, requiring identification novel biomarkers predictive response to this agent. To do so, 22 colon cancer cell lines were screened vitro sensitive resistant identified. In lines, induced G0-G1 arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant preferentially responsive EGF-stimulated growth. Whereas neither protein/mRNA expression nor gene copy number correlated with examination mutation status signaling components downstream showed activating PIK3CA mutations or loss PTEN (PTEN null) more than wild type (WT)/PTEN-expressing (14 ± 5.0% versus 38.5 6.4% inhibition, mean SE; P = 0.008). Consistently, mutant isogenic HCT116 cells increased resistance compared WT controls. Furthermore, mutant/PTEN null Ras/BRAF highly those dual mutations/PTEN (10.8 4.3% 38.8 5.9% respectively; 0.002), indicating constitutive simultaneous activation Ras pathways confers maximal A priori screening tumors could help stratify patients likely benefit from therapy. [Cancer Res 2008;68(6):1953–60]