Figure 8. Rational restoration of Hippo kinase activity resensitizes tumors to PARP inhibition.

(A) Western blot analysis of p-MST1/2 and ZMYND8 across 11 GC cell lines. (B) IC₅₀ values measured from the GC cell lines after they were treated with each PARPi. A group was defined to be sensitive or resistant to PARPi based on whether the IC₅₀ was, respectively, less than or greater than 20 μM. (C) Linear regression analysis of PARPi sensitivity and Hippo kinase activity across the GC cells. (D) Plot showing a dose-dependent suppression of HR repair by SHAP (n = 3). (E) Plots showing that treatment of GC cells with SHAP resensitized the cells to PARPi. Specifically, BGC-823 and AGS cells were each treated with various doses of rucaparib in the presence of 0, 0.5, and 2.0 μM SHAP for 24 hours. (F and G) Results showing that SHAP treatment dramatically enhanced rucaparib-mediated antitumor efficiency in vivo. Nude mice bearing GC tumors were intraperitoneally administered SHAP and rucaparib, either alone or in combination. (F) Tumor size was measured every 3 days, and (G) tumors were photographed and weighed on day 18 (n = 4 mice/group). **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Dunnett’s post hoc test (D and G ) and unpaired Student’s t test (F). See also Supplemental Figure 9.