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Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non–Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment

Authors' Affiliation: Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Jeffrey Settleman, Center for Molecular Therapeutics, Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129. Phone: 617-724-9556; Fax: 617-726-7808; E-mail: Settleman{at}helix.mgh.harvard.edu.

Purpose: Epidermal growth factor receptor (EGFR) kinase inhibitors induce dramatic clinical responses in a subset of non-small cell lung cancer (NSCLC) patients with advanced disease, and such responses are correlated with the presence of somatic activating mutations within the EGFR kinase domain. Consequently, one of these inhibitors, erlotinib, has been Food and Drug Administration-approved as a second- or third-line treatment for chemotherapy-refractory advanced NSCLC. However, responses are typically relatively short-lived due to acquired drug resistance, prompting studies to determine whether first-line treatment with EGFR inhibitors could provide greater clinical benefit. NSCLC-derived cell lines have provided a powerful system for modeling EGFR mutation-correlated sensitivity to EGFR inhibitors and for modeling mechanisms of acquired drug resistance that are observed clinically.

Experimental Design: In a cell culture model of an erlotinib-sensitive EGFR-mutant NSCLC cell line, we tested the hypothesis that prior exposure to platinum agents, a standard component of NSCLC chemotherapy treatment, affects the subsequent response to erlotinib.

Results: Indeed, NSCLC cells initially selected for growth in cisplatin exhibit 5-fold reduced sensitivity to erlotinib, even after propagating the cisplatin-treated cells in the absence of cisplatin for several months. This lingering effect of cisplatin exposure appears to reflect changes in PTEN tumor suppressor activity and persistent EGFR-independent signaling through the phosphatidylinositol 3-kinase/AKT survival pathway.

Conclusions: These preclinical findings suggest that first-line chemotherapy treatment of EGFR-mutant NSCLCs may reduce the benefit of subsequent treatment with EGFR kinase inhibitors and should prompt further clinical investigation of these inhibitors as a first-line therapy in NSCLC.