Fig. 6: HDAC and FGFR inhibition are synergistic in patient-derived FGFR2 fusion-positive ICC models.

A High-throughput small molecule screen inclusive of >2100 clinically relevant anticancer drugs suggest targets synergistic with pemigatinib. Each dot represents a compound plotted against that drug’s synergy score on the y-axis. Smaller differential viability is synonymous with increased synergy. Targets of commonly synergistic pathways are specifically highlighted. B Quisinostat and pemigatinib have synergistic effects on viability in the PDC-DUC18828 model based on MacSynergy II calculation (95% confidence interval). Results are color-coded from purple (most antagonistic) to dark red (most synergistic). C Dose–response curves in the PDC-DUC18828 model shift left with increasing concentrations of pemigatinib, resulting in significant reduction in the IC₅₀ value of quisinostat, concordant with synergy observed in B. All curves are normalized to 0 nM quisinostat under the corresponding concentrations of pemigatinib. D Quisinostat and pemigatinib have synergistic effects on viability in the PDO-DUC18828 model based on MacSynergy II calculation (95% confidence interval). Data are represented as in B. E Dose–response curves in the PDO model shift left with increasing concentrations of pemigatinib, resulting in significant reduction in the IC₅₀ value of quisinostat, concordant with synergy observed in D (normalized as per C). Viability results are normalized to DMSO control and presented as the mean +/− standard deviation (error bars) for three biologically independent replicates. F Quisinostat and pemigatinib have synergistic effects on tumor growth in vivo. Mice bearing subcutaneous xenografts (~125 mm³) were randomized to control (sham/sham gavage with Ora-plus suspension) vs pemigatinib (3 mg/kg oral gavage + sham gavage with Ora-plus suspension) vs quisinostat (16 mg/kg oral gavage + sham gavage with Ora-plus suspension) vs combination treatment (pemigatinib 3 mg/kg oral gavage + quisinostat 16 mg/kg oral gavage) and were treated 5 days per week. Tumor volume was measured 3×/week until study endpoints were reached. Compared to the control cohort (sham/sham), combined treatment with pemigatinib and quisinostat impaired tumor growth by 59.4%, compared to 23.8% with pemigatinib alone and 15.1% with quisinostat alone. Solid brackets (also recognized by arrows) indicate p < 0.05 between treatment arms starting on day 10 of treatment, indicated by the asterisk (*), whereas dashed brackets were not significant. Data are represented as mean +/− standard error of the mean for each experimental condition, consisting of 12 mice each and compared using the Student’s t test.