HDAC5 Deficiency Induces Intrinsic Resistance to KRASG12D Inhibition by Disrupting c-Myc Acetylation-Ubiquitination Homeostasis [RNA-Seq]

We found that HDAC5 deletion significantly enhances intrinsic resistance to MRTX1133 in KRASG12D mutant pancreatic cancer. Mechanistic studies show that HDAC5 deletion promotes resistance to KRASG12D inhibitors by sustaining the activation of the MAPK signaling pathway. RNA-seq analysis was performed on tumors from KPC WT and Hdac5 KO mice, as well as on PANC-1 cells transfected with shNC or shHDAC5, to investigate transcriptomic changes following HDAC5 knockdown.

我们发现，组蛋白去乙酰化酶5（HDAC5）缺失可显著增强KRASG12D突变型胰腺癌对MRTX1133的内在耐药性。机制研究表明，HDAC5缺失通过维持丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路的激活，促进对KRASG12D抑制剂的耐药性。为探究HDAC5敲低后的转录组变化，本研究对KPC野生型（KPC wild-type）及Hdac5基因敲除（Hdac5 knockout, Hdac5 KO）小鼠的肿瘤组织，以及转染了短发卡RNA阴性对照（short hairpin RNA negative control, shNC）或靶向HDAC5的短发卡RNA（shHDAC5）的PANC-1细胞进行了RNA测序（RNA-seq）分析。