获得性耐药仍然是针对癌基因激活途径的治疗的主要挑战。 KRAS 是人类癌症中最常见的突变癌基因，但针对其下游信号激酶的策略未能产生持久的治疗反应。在这里，我们开发了针对 KRAS 突变的胰腺癌、结直肠癌和肺癌的双机制 ERK/MAPK 抑制剂获得性耐药的多种模型，然后探讨了能够抵抗此类药物生存的长期事件。这些研究表明，耐药性的出现继发于大规模的多样化且细胞系特异性的转录适应。转录重编程超出了既定的早期反应，而是代表了一个动态的、进化的过程，经过改进以获得稳定的抗性表型。机制和转化研究表明，对双机制 ERK/MAPK 抑制的抵抗广泛地容易受到表观遗传机制的操纵，特别是介导激酶可以在瓶颈点共同靶向，以防止多样化的、细胞系特异性的抵抗计划。

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.