|Publication Type||Journal Article|
|Year of Publication||2006|
|Authors||Kobayashi, S, Shimamura, T, Monti, S, Steidl, U, Hetherington, CJ, Lowell, AM, Golub, T, Meyerson, M, Tenen, DG, Shapiro, GI, Halmos, B|
|Pages||11389 - 98|
|Keywords||Animals, Antineoplastic Agents, Apoptosis, Blotting, Cancer, Carcinoma, Cell Line, Cyclin-Dependent Kinases, Cyclins, Dose-Response Relationship, Drug, Drug Resistance, Flavonoids, Gene Exp, Gene Expression Profiling, Neoplasm, Non-Small-Cell Lung, Tumor, Western|
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance. The gefitinib-resistant, T790M-mutant H1975 NSCLC cell line undergoes prominent growth arrest and apoptosis when treated with the irreversible EGFR inhibitor, CL-387,785. We did a transcriptional profiling study of mutant EGFR target genes that are differentially expressed in the "resistant" gefitinib-treated and the "sensitive" CL387,785-treated H1975 cells to identify the pivotal transcriptional changes in NSCLC with EGFR-activating mutations. We identified a small subset of early gene changes, including significant reduction of cyclin D1 as a result of EGFR inhibition by CL-387,785 but not by gefitinib. The reduction in cyclin D1 transcription was associated with subsequent suppression of E2F-responsive genes, consistent with proliferation arrest. Furthermore, cyclin D1 expression was higher in EGFR-mutant lung cancer cells compared with cells with wild-type EGFR. EGFR-mutant cells were routinely sensitive to the cyclin-dependent kinase inhibitor flavopiridol, confirming the functional relevance of the cyclin D axis. These studies suggest that cyclin D1 may contribute to the emergence of EGFR-driven tumorigenesis and can be an alternative target of therapy.