Fig. 7: The STAT1-YAP1 axis, through the mevalonate pathway, contributes to the growth of mutant KRAS cells and their resistance to anti-tumor drugs.
a, b HCT116 cells with intact or depleted STAT1 and/or YAP1 expression were subcutaneously transplanted into female nu/nu mice (n = 10 per group). Tumor volume (mm³) was measured over the indicated time course. At the end of the study, tumor tissues from 3 mice were analyzed by IHC to assess H&E staining and the subcellular localization of YAP1 (b). c, d Similarly, HCT116 cells with combined YAP1 and STAT1 deletion or expression were transplanted into nu/nu mice (n = 5 per group). When tumors reached ~200 mm3, mice were treated by oral gavage with either vehicle or cerivastatin (CERI). Tumor growth was monitored over time. Red and blue arrows indicate the start point of treatment of YAP1+/+ STAT1+/+ and YAP1−/− STAT1−/− tumors, respectively. At the endpoint, tumors from 3 mice were subjected to IHC for H&E and YAP1 detection (d). a–d Data represent mean ± SEM. Statistical significance was determined by t-test: *P < 0.05, **P < 0.01, ***P < 0.001. Scale bar in panels b and d: 50 μm and 25 μm (insert image). Quantification graphs panels b and d show Histo (H)-scores for nuclear and cytoplasmic YAP1 staining. e HCT116 xenografts were established in nu/nu mice (n = 5 per group). Upon tumor growth to ~200 mm3 (red arrow), mice received either vehicle, cerivastatin (oral), afatinib (intraperitoneal), or the combination of both. Tumor volume was tracked for the indicated duration. Data represent mean ± SEM. ***P < 0.001 (t-test). f In a similar setup, mice bearing HCT116 xenografts (~200 mm3 tumors) were treated with vehicle, cerivastatin (oral), VT104 (oral), or their combination. Tumor growth was monitored throughout the experiment. Data represent mean ± SEM. **P < 0.01 (t-test). g This schematic model illustrates how the STAT1–YAP1 signaling axis enhances the mevalonate pathway, thereby supporting tumor growth and chemoresistance in mutant KRAS CRC. Inhibiting YAP1-TEAD4 activity (e.g., using VT104) disrupts the SREBP-driven feedback loop that sustains mevalonate pathway activation. Additionally, pharmacological blockade of the mevalonate pathway with statins increases tumor sensitivity to YAP1–TEAD4 inhibition in xenograft models of mutant KRAS CRC.
