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Enhancement of Sensitivity to Tumor Necrosis Factor in Non–Small Cell Lung Cancer Cells with Acquired Resistance to Gefitinib

Authors' Affiliations: ¹ First Department of Internal Medicine and ² Institute of Molecular Oncology, Showa University, Tokyo, Japan; ³ Internal Medicine, Pharmacology Division, National Cancer Center Hospital, National Cancer Center Research Institute, Tokyo, Japan; and ⁴ Gifu University, Gifu, Japan

Requests for reprints: Tohru Ohmori, Institute of Molecular Oncology, Showa University, Hatanodai, 1-5-8, Shinagawa-ku, Tokyo 142-8555, Japan. Fax: 81-3-3784-2299; E-mail: ohmorit{at}med.showa-u.ac.jp.

Tumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor (TNF-). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF- and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF- was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF--induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF--induced Akt phosphorylation and IB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF- in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF- sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF- would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.

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