|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Stegmaier, K, Corsello, SM, Ross, KN, Wong, JS, DeAngelo, DJ, Golub, TR|
|Date Published||2005 Oct 15|
|Keywords||Biomarkers, Tumor, Cell Differentiation, Cell Survival, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Leukemia, Myeloid, Acute, Quinazolines, Receptor, Epidermal Growth Factor, Tumor Cells, Cultured|
Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.
|PubMed Central ID||PMC1895296|
|Grant List||5K08 CA098444-03 / CA / NCI NIH HHS / United States|