Complete remission of TEL-PDGFRB-induced myeloproliferative disease in mice by receptor tyrosine kinase inhibitor SU11657.
The TEL-PDGFRB fusion oncogene is associated with chronic myelomonocytic leukemia (CMML) and results in the expression of a constitutively active tyrosine kinase. SU11657 is a multitargeted selective inhibitor of class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors KIT and FLT3. SU11657 inhibited TEL/PDGFbetaR kinase activity at nanomolar concentrations and inhibited TELPDGFRB-mediated factor-independent growth in myeloblastic 32D cells. Daily oral administration of SU11657 at 40 mg/kg suppressed myeloproliferation and significantly prolonged survival in TELPDGFRB mice treated prior to disease development, as well as in those with large tumor burdens. Our findings suggest that SU11657 or similar agents may have therapeutic potential in humans with hematologic malignancies expressing PDGFR fusion oncogenes.
Cain
Jennifer A
JA
Washington University School of Medicine, Division of Oncology Section, Stem Cell Biology, Campus Box 8007, 660 S Euclid, St Louis, MO 63110, USA.
Grisolano
Jay L
JL
Laird
A Douglas
AD
Tomasson
Michael H
MH
D000818:Animals; D004195:Disease Models, Animal; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D051379:Mice; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009930:Organic Chemicals / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012074:Remission Induction
D015514:Oncogene Proteins, Fusion; D009930:Organic Chemicals; C474557:SU 11657; C120888:TEL-PDGFRbeta fusion protein, human; D020794:Receptor Protein-Tyrosine Kinases