Multi-omics characterization of MEK inhibitor resistant pancreatic cancer based on a genetically engineered mouse model-derived in vitro system

Tumor heterogeneity and therapy resistance are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Emerging evidence supports treatment-induced resistance to be a multifactorial process mediated by cellular plasticity involving epigenetic regulation. Here, we used a multi-omics approach to analyze in detail molecular mechanisms underlying MEK inhibitor (MEKi) resistance. Therefore, we characterized different cell stages (parental, MEKi resistant, reverted after different passages of drug withdrawal) in primary cell lines derived from a genetic PDAC mouse model, thereby minimizing inter-individual heterogeneity that could distort genome-wide analyses. RNA-sequencing of six primary murine pancreatic ductal adenocarcinoma cell lines. Three to four differrent cell stages (MEKi treatment naive, MEKi resistant, MEKi resistant and drug withdrawal for 5 or 12 passages) were analyzed

肿瘤异质性与治疗耐药性是胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的核心生物学标志。现有研究证据表明，治疗诱导的耐药性是一个多因素过程，由涉及表观遗传调控的细胞可塑性所介导。本研究采用多组学策略，深入解析了MEK抑制剂（MEK inhibitor, MEKi）耐药的潜在分子机制。为此，我们对源自基因工程PDAC小鼠模型的原代细胞系的不同细胞状态（亲本细胞、MEKi耐药细胞、停药传代后恢复的细胞）进行了特征鉴定，以最大限度降低可能干扰全基因组分析的个体间异质性。本研究对6株小鼠原代胰腺导管腺癌细胞系开展了RNA测序。共分析了3至4种不同的细胞状态：未接受MEKi处理的亲本细胞、MEKi耐药细胞，以及耐药后分别停药传代5代或12代的恢复细胞。