PGE2-stimulated proliferation of NSCLC cells is epidermal growth factor receptor-independent and resistant to erlotinib.

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The Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in a variety of malignancies and plays an important role in tumor cell growth, proliferation and metastasis. Because of its important role in tumor progression, EGFR is a promising target for cancer therapy. However, only a limited population of cancer patients responds to EGFR inhibitor therapy. Recent studies have linked sensitivity to EGFR TK inhibitors to activating somatic mutations in the TK domain observed in some non-small cell lung cancer (NSCLC) patients. Other studies have focused on the cross-talk between the downstream components of the EGFR pathway and other signal transduction pathways that can overcome pharmacological inhibition of EGFR. Cyclooxygenase 2 (COX-2) is often upregulated in a wide variety of human cancers including lung cancer and is linked to all stages of tumorigenesis. We have found that prostaglandin E2 (PGE2), the major COX-2 metabolite, is able to cross-activate the EGFR pathway in a subset of NSCLC cell lines through its G-protein coupled receptors in an EGFR-independent manner. This cross-activation is resistant to EGFR inhibitors including erlotinib (Tarceva®) and is not evident in bronchial epithelial cells. The functional manifestation of such trans-activation was an enhanced NSCLC cell proliferation in response to PGE2 treatment that was resistant to EGFR inhibition, suggesting that COX-2 overexpression may contribute to EGFR inhibitor resistance in NSCLC. We tested a panel of NSCLC cell lines for sensitivity to erlotinib and celecoxib (Celecoxib®) alone or in combination. We have found that combination treatment of NSCLC cells with COX-2 and EGFR inhibitors significantly reduces cell proliferation compared to either drug alone. These results provide a strong rationale for the combined use of COX-2 and EGFR inhibitors in NSCLC therapy. Erlotinib was generously provided by OSI Pharmaceuticals (Farmingdale, NY). This study was supported by the UCLA SPORE In Lung Cancer NIH P50 CA90388, Tobacco-Related Disease Research Program grant #12FT-0061 (K.K.) and VA Career Development Award, ASCO Young Investigator Award, STOP Cancer Memorial Award (K.L.R.).