Article Figures & Data
Figures
- Figure 1.
Ponatinib inhibits FGFR1–4-dependent cell growth in engineered Ba/F3 cells. Ba/F3 cells expressing a recombinant TEL/kinase domain fusion protein for FGFR1–4 or empty vector (parental Ba/F3) were used to evaluate compound selectivity and potency. A, cells were incubated with the indicated concentrations of compound for 72 hours and cell viability assessed. Data are presented as means (±SD) from 3 experiments. B, Ba/F3 cells were treated for 1 hour, lysates immunoblotted for phospho-FGFR (left), and then reprobed for total levels (right) of the respective FGFR. Similar results were obtained in 2 independent experiments.
- Figure 2.
Ponatinib inhibits mutant FGFR2 in endometrial cancer models. A, endometrial cancer cells were incubated with ponatinib for 72 hours and cell growth assessed (MFE-280 cells were assayed in FBS-free media in the presence of 25 ng/mL FGF2 and 10 μg/mL heparin). Data are presented as means (±SD) from 3 experiments. B, AN3CA cells were treated for 1 hour and lysates immunoblotted for phospho and total protein levels. Similar results were obtained in 2 independent experiments. C, AN3CA xenografts were established and mice dosed for 11 days. Mean tumor volumes (±SEM) are plotted. D, pharmacodynamic effect of ponatinib in AN3CA tumor xenografts. Each lane represents a separate animal. Mean plasma ponatinib levels (±SD) are shown. ND, not determined.
- Figure 3.
Ponatinib inhibits mutant FGFR3 in bladder cancer models. A, bladder cancer cells were incubated with ponatinib for 72 hours and cell growth assessed. Data are presented as means (±SD) from 3 experiments. B, UMUC14 cells were treated for 1 hour and lysates immunoblotted for phospho-FRS2α and GAPDH. Similar results were obtained in 2 independent experiments. C, UMUC14 xenografts were established and mice dosed for 21 days. Mean tumor volumes (±SEM) are plotted. D, pharmacodynamic effect of ponatinib in UMUC14 tumor xenografts. Each lane represents a separate animal. Mean plasma ponatinib levels (±SD) are shown. ND, not determined.
- Figure 4.
Ponatinib inhibits amplified FGFR2 in gastric cancer models. A, gastric cancer cells were incubated with ponatinib for 72 hours and cell growth assessed. Data are presented as means (±SD) from 3 experiments. B, SNU16 cells were treated for 1 hour and lysates immunoblotted for phospho-and total protein levels. Similar results were obtained in 2 independent experiments. C, SNU16 xenografts were established and mice were dosed for 21 days. Mean tumor volumes (±SEM) are plotted. D, pharmacodynamic effect of ponatinib in SNU16 tumor xenografts. Each lane represents a separate animal. Mean plasma ponatinib levels (±SD) are shown. ND, not determined.
- Figure 5.
Ponatinib inhibits amplified FGFR1 and FGFR2 in breast, lung, and colon cancer models. Cancer cells were incubated with ponatinib for 72 hours and cell growth assessed. Data are presented as means (±SD) from 3 experiments. A, ER-positive breast cancer cells with and without FGFR1 amplification. B, ER-negative breast cancer cells with and without FGFR2 amplification. C, lung cancer cells with and without FGFR1 amplification. D, colon cancer cells with and without FGFR2 amplification.
Tables
- Table 1.
Activity of ponatinib in a panel of FGFR-amplified or -mutated cancer cell lines
Phospho-FGFR IC50, nmol/L Cell growth GI50, nmol/L Cancer Cell line FGFR status (ref.) Ponatinib Ponatinib Dovitinib Cediranib BIBF 1120 Brivanib Endometrial AN3CA FGFR2 N549K (16) 4 14 112 40 886 >1,000 MFE-296 FGFR2 N549K (16) 3 61 359 210 980 >1,000 MFE-280a FGFR2 S252W (16) 13 35 350 84 258 197 Bladder MGH-U3 FGFR3 Y375C (41) 40b 181 204 >1,000 >1,000 >1,000 UMUC14 FGFR3 S249C (41–42) 33b 103 182 168 625 >1,000 Gastric SNU16 FGFR2 amp (43, 45) 20 25 99 142 473 >1,000 KATO III FGFR2 amp (43) 21 10 64 86 233 865 Breast MDA-MB-134 FGFR1 amp (7) 7 23 186 297 226 >1,000 SUM 52PE FGFR2 amp (8) 6 14 63 76 364 >1,000 MFM-223 FGFR2 amp (8) 7 69 411 416 >1,000 >1,000 Lung H1581 FGFR1 amp (4) 13 32 216 168 427 >1,000 DMS-114 FGFR1 amp (4) 30 108 818 911 >1,000 >1,000 H520 FGFR1 amp (4) 7 155 >1,000 >1,000 >1,000 >1,000 Colon H716 FGFR2 amp (14) 9 7 33 49 178 598
Supplementary Data
Files in this Data Supplement:
- Supplementary Methods, Figure Legends 1-6 - PDF file - 89K
- Supplementary Figures 1-6 - PDF file - 457K
- Supplementary Table 1 - PDF file - 73K
Volume 11, Issue 3
