Title: Simultaneous inhibition of EGFR and c-Met pathways in a panel of NSCLC cell lines
Abstract: 22223 Background: The EGFR inhibitor, erlotinib, prolongs survival in chemotherapy-resistant NSCLC patients, although < 50% respond. Reportedly, simultaneous inhibition of EGFR (by gefitinib) and c-Met (by PHA-665752) was antiproliferative in a line selected for resistance to gefitinib alone. We hypothesized that in lines not previously exposed to either agent, simultaneous inhibition of EGFR and c-Met pathways would slow NSCLC growth more than targeting either single pathway. Methods: NSCLC lines were cultured in 96-well plates at 5000 cells/well. After 24 h, erlotinib (OSI) and the c-Met inhibitor SU11274 (Sigma) were added. Cells were recovered 3–5 d later by trypsinization and counted by hemacytometer. Receptor activation and signaling were studied in A549 by Western blotting following serum deprivation, incubation with inhibitors (3.5 h) and EGF (15 m). Results: In A549, E2 suppressed EGFR phosphorylation (pY1068), and S3 suppressed c-Met pY1230/1234/1235, confirming pathway targeting. Both drugs suppressed phosphorylation of Akt at S473 and Erk1/2 at T202/Y204, consistent with growth inhibition. Conclusions: For all lines except Calu3, S5 was more antiproliferative than E10, demonstrating that c-Met is a target of interest for NSCLC. By the Bliss criterion, the effect of drugs acting independently should equal the product of the effects of each drug alone. Antiproliferation was independent or nearly so (60% to 167% of prediction) for 14/18 combinations with one or both drugs at their lesser concentrations (bold values). Except in H1437, the combination S5E10 was more potent than either single agent, but weaker than predicted by independence. We speculate that EGFR and c-Met signaling pathways overlap in NSCLC, or E10 and S5 share off-target effects. Lack of pronounced synergism in drug-naive cells distinguishes de novo from acquired resistance to EGFR inhibition. We conclude that combined use of EGFR and c-Met inhibitors is rational even in front-line NSCLC therapy, if dose-limiting toxicities of the drugs differ. Relative proliferation of NSCLC lines incubated with erlotinib (E) and/or SU11274 (S). Cell Line S1 S5 E2 E10 S1E2 S5E2 S1E10 S5E10 A549 0.74 0.04 0.72 0.26 0.52 0.13 0.29 0.08 Calu3 0.88 0.23 0.16 0.15 0.36 0.22 0.18 0.10 H1299 0.81 0.18 0.66 0.24 0.63 0.20 0.25 0.14 H1437 0.97 0.10 0.90 0.37 0.58 0.20 0.46 0.12 H1975 0.65 0.10 0.65 0.23 0.61 0.04 0.23 0.06 H2122 0.64 0.07 0.66 0.26 0.44 0.06 0.13 0.04 Proliferation P = # cells drug/# cells DMSO. E2 = 2 uM erlotinib, etc. 1 SD = 4–11% of P. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration OSI Oncology
Publication Year: 2008
Publication Date: 2008-05-20
Language: en
Type: article
Indexed In: ['crossref']
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Cited By Count: 2
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