Page 185 - Haematologica April 2020

EZH2 inhibition synergies with CDK9 inhibition
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Figure 4. Combined anti-tumor effect of CDKI-73 and EPZ6438/GSK126 in vitro and in vivo. (A) The level of H3K27me3 in Pfeiffer and Karpass-422 cells after treat- ed with CDKI-73, and EPZ6438/GSK126 alone or in combination. Cells were pretreated with 0.5 μM EPZ6438/GSK126 alone for 24 hours (h), and then treated in combination with 0.1 μM CDKI-73 for an additional 24 h. (B) The relative mRNA levels of GATA4, CDKN2A, HOXC8, and TNFRSF21 in Pfeiffer cells when pretreated with 0.5 μM EPZ6438/GSK126 alone for 24 h, then treated in combination with 0.1 μM CDKI-73 for additional 6 h. (C) Average combination index (CI) values. Diffuse large B-cell lymphoma (DLBCL) cells were treated with different doses of CDKI-73 and EPZ6438/GSK126 alone or in combination for 72 h. (D) The CI values of nine different DLBCL cell lines. The combination groups were pretreated with a fixed dose of EPZ6438 or GSK126 for 72 h and then both CDKI-73 and combination groups were treated with increasing doses of CDKI-73 for additional 72 h. (E) The dose-response curves of Will-1, Will-2, and SU-DHL-6 cell lines. The combination groups were pretreated with a fixed dose of EPZ6438 or GSK126 for seven days and then both CDKI-73 and combination groups were treated with increasing doses of CDKI- 73 for additional 72 h. (F-G) Relative tumor volume (RTV) and average body weight of nude mice treated with 50 mg/kg CDKI-73 and 50 mg/kg EPZ66438 alone or together with inoculated Pfeiffer and SU-DHL-6 cells. Data are expressed as the mean + standard error of the mean (SEM). (H) The level of H3K27me3 detected in Pfeiffer xenografts at the end of the in vivo experiment. C: CDKI-73; E: EPZ6438; G: GSK126. All data are representative of at least three independent experiments. ***P<0.001, **P<0.01, *P<0.05. Mut: mutant; wt: wild-type.
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