Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma.
We have previously shown that dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the t(4;14) translocation is a primary event in multiple myeloma (MM) and that activating mutations of FGFR3 are acquired in some cases. We describe here inhibition of wild-type (WT) and constitutively activated mutant FGFR3 autophosphorylation by the small molecule inhibitor, PD173074. Inhibition of FGFR3 in human myeloma cell lines was associated with decreased viability and tumor cell growth arrest. Further, morphologic, phenotypic, and functional changes typical of plasma cell (PC) differentiation, including increase in light-chain secretion and expression of CD31, were observed and this was followed by apoptosis. Finally, using a mouse model of FGFR3 myeloma, we demonstrate a delay in tumor progression and prolonged survival of mice treated with PD173074. These results indicate that inhibition of FGFR3, even in advanced disease associated with multiple genetic changes, may allow the cell to complete its developmental program and render it sensitive to apoptotic signals. In addition, this represents the validation of a therapeutic target in MM that may benefit patients who have a very poor prognosis with currently available treatments.
Trudel
Suzanne
S
Department of Medicine, Weill Medical College and Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Ely
Scott
S
Farooqi
Yildiz
Y
Affer
Maurizio
M
Robbiani
Davide F
DF
Chesi
Marta
M
Bergsagel
P Leif
PL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous
C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3