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Blood DOI:10.1182/blood-2005-02-0488

Gefitinib induces myeloid differentiation of acute myeloid leukemia.

Publication TypeJournal Article
Year of Publication2005
AuthorsStegmaier, K, Corsello, SM, Ross, KN, Wong, JS, DeAngelo, DJ, Golub, TR
Date Published2005 Oct 15
KeywordsBiomarkers, 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.


Alternate JournalBlood
PubMed ID15998836
PubMed Central IDPMC1895296
Grant List5K08 CA098444-03 / CA / NCI NIH HHS / United States