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Transcriptional Profiling Identifies Cyclin D1 as a Critical Downstream Effector of Mutant Epidermal Growth Factor Receptor Signaling

¹ Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and ² Department of Pathology, Harvard Medical School; ³ Department of Medical Oncology, Dana-Farber Cancer Institute; ⁴ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; ⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ⁶ Howard Hughes Medical Institute, Boston, Massachusetts; ⁷ The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; and ⁸ University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Daniel G. Tenen, Harvard Institutes of Medicine, Room 954, 77 Avenue Louis Pasteur, Boston, MA 02115. Phone: 617-667-5561; Fax: 617-667-3299; E-mail: dtenen{at}bidmc.harvard.edu or Geoffrey I. Shapiro, Department of Medical Oncology, Dana-Farber Cancer Institute, Dana 810A, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4942; Fax: 617-632-1977; E-mail: geoffrey_shapiro{at}dfci.harvard.edu.

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. (Cancer Res 2006; 66(23): 11389-98)

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