Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.
The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.
Grand
E K
EK
Wessex Regional Genetics Laboratory, Salisbury, UK.
Chase
A J
AJ
Heath
C
C
Rahemtulla
A
A
Cross
N C P
NC
D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D014178:Translocation, Genetic
C115711:PD 173074; D011743:Pyrimidines; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; C496365:FGFR3 protein, human; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3