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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2841-2848.
Prepublished online as a Blood First Edition Paper on July 5, 2005; DOI 10.1182/blood-2005-02-0488.
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NEOPLASIA
Gefitinib induces myeloid differentiation of acute myeloid leukemia
Kimberly Stegmaier,
Steven M. Corsello,
Kenneth N. Ross,
Jenny S. Wong,
Daniel J. DeAngelo, and
Todd R. Golub
From the Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA; The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA; Howard Hughes Medical Institute, Chevy Chase, MD; and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
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. (Blood. 2005;106: 2841-2848)
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