HDAC3是组蛋白去乙酰化酶（HDAC）抑制剂在癌症疗法中临床开发的主要靶点之一，但在实体瘤中HDAC3的体内作用是未知的。我们确定了HDAC3在Kras突变肺癌中的关键作用。使用基因工程小鼠模型（GEMM），我们发现HDAC3在体内对肺肿瘤生长非常关键。我们发现，HDAC3指导并增强肺癌谱系转录因子NKX2-1的转录效应，从而介导一组共同的靶基因的表达。我们确定了FGFR1是HDAC3的一个重要但以前未被发现的靶标。利用这一点，我们确定Kras/LKB1突变细胞抵抗MEK抑制剂trametinib时，一个依赖于HDAC3的转录组变得过度活化，但可以通过用HDAC1 / HDAC3抑制剂entinostat治疗来逆转这种现象。我们发现entinostat与trametinib联合治疗可在Kras/LKB1 GEMM中产生治疗效果。

HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in Kras-mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1-mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM.