Albert Einstein Cancer Center

PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

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 a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To this end, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines. Cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. This study suggests that assessment of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutations may be of value in the prediction of response to cetuximab

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