Malignant pleural mesothelioma (MPM) is a rare malignancy with no known curative modality. Approximately 70% of MPMs have high levels of expression of the epidermal growth factor receptor (EGFR), and a subset of cell lines derived from MPM patients express both EGFR and transforming growth factor alpha, suggesting an autocrine role for EGFR in MPM. We have determined the effects of EGFR inhibition in MPM cell lines in vitro, using four MPM cell lines derived from previously untreated patients with epithelial (H2461 and H2591), sarcomatoid (H2373), and biphasic (MSTO-211H) MPM. All four cell lines expressed EGFR at levels comparable with the non-small cell lung carcinoma (NSCLC) cell line A549, as shown by Western blot analysis. ZD1839 significantly inhibited epidermal growth factor-dependent cell signaling including phosphorylation of AKT and extracellular signal-regulated kinases 1 and 2 in all MPM cell lines. Furthermore, treatment with ZD1839 led to a significant dose-dependent reduction of colony formation (41-89% at 10 microM) when MPM cells were grown in soft agarose. MSTO-211H, H2461, and H2373 were more sensitive to the growth-inhibitory effects of ZD1839 than was the NSCLC cell line A549, whereas H2591 had similar sensitivity to A549. This variability in growth-inhibitory effects is not related to the amount of EGFR present on MPM cells or to the degree of inhibition of EGFR phosphorylation by ZD1839. We show that H2373 MPM cells, which show 89% growth inhibition at 10 microM ZD1839, undergo a dose-dependent arrest at the G(1)-S phase of the cell cycle and a corresponding increase in p27 levels. However, H2591 cell lines, which show 41% growth inhibition at 10 microM ZD1839, undergo no significant cell cycle changes or changes in p27 levels. Our findings demonstrate that in vitro, ZD1839 is as effective or more effective against MPM cell lines as it is against the NSCLC cell line A549 and suggest that ZD1839 may be an effective therapeutic option for patients with MPM.