Bromodomain and extraterminal (BET) proteins are promising therapeutic targets for hematological and solid tumors. However, BET inhibitor monotherapy did not show a significant therapeutic benefit for hepatocellular carcinoma (HCC) in preclinical trials. Here, we identified YAP/TAZ genes, as determinants for sensitivity to BET inhibitors. YAP/TAZ expression, especially TAZ, promote resistance to BET inhibitor. In addition, we analyzed that the mRNA level of PDE5 was positively correlated with YAP/TAZ based on TCGA database and demonstrated tadalafil, a PDE5 inhibitor, could block YAP/TAZ protein expression by activating Hippo pathway. Cotreatment with tadalafil and JQ-1 synergistically reduced YAP/TAZ protein expression, suppressed proliferation and induced G0-G1 arrest of cultured HCC cells. JQ-1 alone does not show significant benefits in a mouse model of HCC induced by c-Myc/N-Ras plasmids. In contrast, the combination, tadalafil and JQ-1, successfully suppressed tumor progression, enhanced antitumor immunity by improving the ratio of activated CD8 and extended the survival time of mice. Our data define the key role of YAP/TAZ in mediating resistance to BET inhibitor, described the PDE5/PKG/Hippo/YAP/TAZ axis and identified a common clinical drug that can be developed as an effective combined strategy to overcome BET inhibitor resistance in MYC/Ras-driven HCC.

溴结构域和末端外 (BET) 蛋白是血液学和实体瘤的有希望的治疗靶点。然而，在临床前试验中，BET 抑制剂单一疗法并未显示出对肝细胞癌 (HCC) 的显着治疗益处。在这里，我们确定了 YAP/TAZ 基因，作为对 BET 抑制剂敏感性的决定因素。YAP/TAZ 表达，尤其是 TAZ，促进对 BET 抑制剂的抗性。此外，我们基于 TCGA 数据库分析了 PDE5 的 mRNA 水平与 YAP/TAZ 呈正相关，并证明 PDE5 抑制剂他达拉非可以通过激活 Hippo 通路来阻断 YAP/TAZ 蛋白的表达。他达拉非和 JQ-1 共同处理可协同降低 YAP/TAZ 蛋白表达，抑制增殖并诱导培养的 HCC 细胞的 G0-G1 期阻滞。在由 c-Myc/N-Ras 质粒诱导的 HCC 小鼠模型中，单独使用 JQ-1 并没有显示出显着的益处。相比之下，他达拉非和 JQ-1 的组合成功地抑制了肿瘤进展，通过提高活化 CD8 的比例增强了抗肿瘤免疫并延长了小鼠的存活时间。我们的数据定义了 YAP/TAZ 在介导 BET 抑制剂耐药性中的关键作用，描述了 PDE5/PKG/Hippo/YAP/TAZ 轴，并确定了一种常见的临床药物，可以开发作为克服 BET 抑制剂耐药性的有效组合策略。 MYC/Ras 驱动的 HCC。