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
Read ManuscriptAbstract
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
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 |