Gefitinib (Iressa) induces myeloid differentiation of acute myeloid leukemia

Blood. 2005 Oct 15;106(8):2841-8.. Published: 2005.10.14

Kimberly Stegmaier, Steven M. Corsello, Kenneth N. Ross, Jenny S. Wong, Daniel J. DeAngelo, Todd R. Golub

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Abstract

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 4,5-dianilinophthalimide (DAPH1), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here, we report that the FDA-approved EGFR inhibitor gefitinib (Iressa) similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphological 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.

Keywords: AML cancer chemical genomics leukemia small molecule library screen

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Supplemental Data

Description Link/Filename
Plain text file describing available supplementary information README
Manuscript blank.pdf
Microsoft Excel sheet with supplementary information StegmaierSupplementalData050516.xls
Gefitinib treated HL-60 cell line data Iressa_HL60_MeansScaling.res
Gefitinib treated Kasumi cell line data Iressa_Kasumi_041201_ams.res
Patient 1 (M3-AML) sample data Iressa_Patient1_ams.gct
Patient 2 (M5-AML) sample data Iressa_Patient2_ams.res
Patient 7 (M4-AML) sample data Iressa_Patient7_ams.res
Primary patient AML cells sample data Myeloid_Screen1_newData_021203_ams.AML_poly_mono.gct
Gefitinib treated HL-60 cell line data CEL files Iressa_HL60_CEL_files.zip
Gefitinib treated Kasumi cell line data CEL files Iressa_Kasumi_CEL_files.zip
Patient 1 (M3-AML) sample data CEL files Iressa_Patient1_CEL_files.zip
Patient 2 (M5-AML) sample data CEL files Iressa_Patient2_CEL_files.zip
Patient 7 (M4-AML) sample data CEL files Iressa_Patient7_CEL_files.zip
Primary patient AML cells sample data CEL files Primary_Patient_AML_CEL_files.zip
Manuscript Figure 1 Stegmaier_Fig1_Final.pdf
Manuscript Figure 2 Stegmaier_Fig2_Final.pdf
Manuscript Figure 3 Stegmaier_Fig3_Final.pdf
Manuscript Figure 4 Stegmaier_Fig4_Final.pdf
Manuscript Figure 5 Stegmaier_Fig5_Final.pdf
Manuscript Figure 6 Stegmaier_Fig6_Final.pdf