Fig. 7: HDAC and FGFR inhibition synergistically inhibit proliferation and enhance apoptosis and impair FGFR-dependent signaling. | npj Precision Oncology

Fig. 7: HDAC and FGFR inhibition synergistically inhibit proliferation and enhance apoptosis and impair FGFR-dependent signaling.

From: Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies

Fig. 7

A Quisinostat and pemigatinib synergistically lower the proliferative index (Ki-67) in the PDC-DUC18828 model. The percentage of Ki-67-positive cells was determined and flow cytometry data are shown on the left with corresponding Ki-67 index for each condition shown in the bar graph on the right. Compared to DMSO control, 50 nM pemigatinib decreases the Ki-67 index by ~30%, 100 nM quisinostat decreases the Ki-67 index by ~24%, while 50 nM pemigatinib + 100 nM quisinostat (Pemi + Qui) synergistically decrease the Ki-67 index by ~53% (**p < 0.01 and ***p < 0.001). B Quisinostat and pemigatinib synergistically lower the Ki-67 in the PDO-DUC18828 model. Data are presented as in A. Compared to DMSO control, 10 nM pemigatinib decreases the Ki-67 by ~36%, 25 nM quisinostat decreases the Ki-67 by ~24%, while 10 nM pemigatinib + 25 nM quisinostat (Pemi + Qui) synergistically decreases the Ki-67 index by ~50% (*p < 0.05 and **p < 0.01). C, D Quisinostat and pemigatinib synergistically enhance apoptosis in the PDC- and PDO-DUC18828 models, respectively. In both models, under the conditions indicated, combined inhibition of HDAC and FGFR increases the proportion of apoptotic cells, especially late-stage apoptosis, but also the early apoptotic population, compared to monotherapy or DMSO control. Q1, dead cells; Q2, late apoptotic/dead cells; Q3, early-apoptotic cells; Q4, healthy cells. E Western blot analysis of PDC-DUC18828 with pemigatinib (2P = 2 nM) monotherapy, quisinostat (50Q = 50 nM) monotherapy, and combination therapy (P + Q = 2 nM pemigatinib + 50 nM quisinostat). Compared to DMSO control, quisinostat monotherapy increases FGFR2, FRS2, MEK, and ERK activation, while pemigatinib monotherapy inhibits FGFR2 signaling, including downstream nodes, FRS2, MEK, and ERK. Combination therapy similarly impairs FGFR2, FRS2, MEK, and ERK activity. Neither monotherapy nor combination therapy alter AKT activity.

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