In vitro activity of the multitargeted receptor tyrosine kinase inhibitor sunitinib against multiple myeloma cell lines is not predictive of in vivo xenograft response
Year: 2008
Session type: Poster / e-Poster / Silent Theatre session
Northern Institute for Cancer Research, Newcastle University, Newcastle, UK
Abstract
The t(4;14) gene translocation in 15% of Multiple Myeloma (MM) patients leads to the ectopic expression of FGFR3 and is associated with a poor prognosis, suggesting that FGFR3 is a therapeutic target in this disease.
In in vitro kinase assays, sunitinib has been identified as a potent FGFR3 inhibitor (IC50 120 - 300nM). An interleukin 3 (IL-3) independent Baf/3 cell line engineered to express the ZNF198-FGFR1 fusion protein, and t(4;14) positive and negative MM cell lines, were used to screen for growth inhibition using the MTS assay. Sunitinib differentially inhibited the growth of Baf/3 cell transfectants compared to wild type cells, (GI50 value of 730nM versus 2.7µM). Similarly, sunitinib induced differential growth inhibition of t(4:14) positive cell lines, (GI50 1.2µM compared to 4-5µM for t(4:14) negative cell lines). The in vivo efficacy of sunitinib was assessed using JIM1 (t(4:14) positive) and RPMI8226 (t(4:14) negative) subcutaneous xenografts grown in mice treated with vehicle control or 40mg/kg sunitinib daily by oral administration for 21 days. Treatment with sunitinib gave only a minor 2 day growth delay in the t(4:14) positive JIM1 xenograft model, whereas marked antitumour activity was observed in the t(4:14) negative RPMI8226 model with at least a 15 day growth delay.
These results suggest that the in vivo efficacy of sunitinib is not solely due to cellular determinants, but is dependent on other factors such as, potentially, host stroma interactions. Furthermore, these studies caution against using the t(4:14) translocation as a predictive biomarker for sunitinib sensitivity in MM.
The t(4;14) gene translocation in 15% of Multiple Myeloma (MM) patients leads to the ectopic expression of FGFR3 and is associated with a poor prognosis, suggesting that FGFR3 is a therapeutic target in this disease.
In in vitro kinase assays, sunitinib has been identified as a potent FGFR3 inhibitor (IC50 120 - 300nM). An interleukin 3 (IL-3) independent Baf/3 cell line engineered to express the ZNF198-FGFR1 fusion protein, and t(4;14) positive and negative MM cell lines, were used to screen for growth inhibition using the MTS assay. Sunitinib differentially inhibited the growth of Baf/3 cell transfectants compared to wild type cells, (GI50 value of 730nM versus 2.7µM). Similarly, sunitinib induced differential growth inhibition of t(4:14) positive cell lines, (GI50 1.2µM compared to 4-5µM for t(4:14) negative cell lines). The in vivo efficacy of sunitinib was assessed using JIM1 (t(4:14) positive) and RPMI8226 (t(4:14) negative) subcutaneous xenografts grown in mice treated with vehicle control or 40mg/kg sunitinib daily by oral administration for 21 days. Treatment with sunitinib gave only a minor 2 day growth delay in the t(4:14) positive JIM1 xenograft model, whereas marked antitumour activity was observed in the t(4:14) negative RPMI8226 model with at least a 15 day growth delay.
These results suggest that the in vivo efficacy of sunitinib is not solely due to cellular determinants, but is dependent on other factors such as, potentially, host stroma interactions. Furthermore, these studies caution against using the t(4:14) translocation as a predictive biomarker for sunitinib sensitivity in MM.
