OBJECTIVE: Dysregulation of signaling pathways leading to enhanced cell proliferation and resistance to apoptosis is frequent in acute myeloid leukemia (AML). The effectiveness of inhibiting two such pathways, the phosphatidylinosityl-3-kinase pathway via the intermediate integrin-linked kinase (ILK), and FMS-like tyrosine kinase-3 (FLT-3) signaling pathway in killing AML cells was studied. MATERIALS AND METHODS: AML colony-forming cell (CFC) assays were used to determine the effects of a small molecule inhibitor of both ILK and FLT-3 (QLT0267) on poor prognosis primary AML sample viability. Kinase assays and Western blots were used to analyze effects of the compound on target molecules. RESULTS: In 31/36 AML blast samples p-Akt was detected indicating phosphatidylinosityl-3-kinase activation. ILK was ubiquitously and FLT-3 abundantly expressed. Downregulation of ILK in the AML cell line TF-1 using small interfering RNA caused >or= 50% CFC death, suggesting ILK inhibition might also be toxic to primary AML cells. In vitro kinase assays on three AML samples showed inhibition of both ILK and FLT-3 by QLT0267. Treatment of AML patient blast cells (n=27) with QLT0267, caused a dose- and time-dependent downregulation of p-Akt and kill of AML-CFC with AML samples containing FLT-3 mutations being more sensitive to QLT0267 than those without. AML samples were more sensitive to QLT0267 killing than normal bone marrow (IC(50)=3 microM, vs 10 microM for AML-CFC and normal CFC, respectively, n=5). CONCLUSION: Combined inhibition of ILK and FLT-3 with a small molecule kinase inhibitor can achieve selective targeting of AML rather than normal hematopoietic progenitors.
OBJECTIVE: Dysregulation of signaling pathways leading to enhanced cell proliferation and resistance to apoptosis is frequent in acute myeloid leukemia (AML). The effectiveness of inhibiting two such pathways, the phosphatidylinosityl-3-kinase pathway via the intermediate integrin-linked kinase (ILK), and FMS-like tyrosine kinase-3 (FLT-3) signaling pathway in killing AML cells was studied. MATERIALS AND METHODS:AML colony-forming cell (CFC) assays were used to determine the effects of a small molecule inhibitor of both ILK and FLT-3 (QLT0267) on poor prognosis primary AML sample viability. Kinase assays and Western blots were used to analyze effects of the compound on target molecules. RESULTS: In 31/36 AML blast samples p-Akt was detected indicating phosphatidylinosityl-3-kinase activation. ILK was ubiquitously and FLT-3 abundantly expressed. Downregulation of ILK in the AML cell line TF-1 using small interfering RNA caused >or= 50% CFC death, suggesting ILK inhibition might also be toxic to primary AML cells. In vitro kinase assays on three AML samples showed inhibition of both ILK and FLT-3 by QLT0267. Treatment of AMLpatient blast cells (n=27) with QLT0267, caused a dose- and time-dependent downregulation of p-Akt and kill of AML-CFC with AML samples containing FLT-3 mutations being more sensitive to QLT0267 than those without. AML samples were more sensitive to QLT0267 killing than normal bone marrow (IC(50)=3 microM, vs 10 microM for AML-CFC and normal CFC, respectively, n=5). CONCLUSION: Combined inhibition of ILK and FLT-3 with a small molecule kinase inhibitor can achieve selective targeting of AML rather than normal hematopoietic progenitors.
Authors: N Sandhöfer; K H Metzeler; M Rothenberg; T Herold; S Tiedt; V Groiß; M Carlet; G Walter; T Hinrichsen; O Wachter; M Grunert; S Schneider; M Subklewe; A Dufour; S Fröhling; H-G Klein; W Hiddemann; I Jeremias; K Spiekermann Journal: Leukemia Date: 2014-10-17 Impact factor: 11.528
Authors: Marina Y Konopleva; Roland B Walter; Stefan H Faderl; Elias J Jabbour; Zhihong Zeng; Gautam Borthakur; Xuelin Huang; Tapan M Kadia; Peter P Ruvolo; Jennie B Feliu; Hongbo Lu; Lakiesha Debose; Jan A Burger; Michael Andreeff; Wenbin Liu; Keith A Baggerly; Steven M Kornblau; L Austin Doyle; Elihu H Estey; Hagop M Kantarjian Journal: Clin Cancer Res Date: 2014-02-28 Impact factor: 12.531