Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.

中文翻译：

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干扰素基因表达的抑制克服了 KRAS 突变结直肠癌对 MEK 抑制的耐药性。


尽管 MEK 抑制剂 (MEKi) 曲美替尼在 BRAF 突变黑色素瘤中显示出临床活性，但未能在 KRAS 突变结直肠癌中显示出临床益处。为了确定 MEKi 耐药机制，我们对 MEKi 敏感与 MEKi 耐药结直肠癌细胞系进行了药物基因组学分析。引人注目的是，干扰素和炎症相关的基因集在表现出对 MEK 抑制的内在和获得性抗性的细胞系中富集。 bromodomain 抑制剂 JQ1 抑制干扰素刺激基因 (ISG) 的表达，并与 MEK 抑制剂联合使用，在 MEKi 耐药结直肠癌细胞系中表现出协同作用并诱导细胞凋亡。 ISG 表达在患者来源的类器官模型中得到证实，该模型对曲美替尼表现出耐药性，并通过 JQ1 联合治疗重新敏化。在结直肠癌的体内模型中，联合治疗显着抑制肿瘤生长。我们的研究结果为 KRAS 突变结直肠癌（因其炎症性质而闻名）中对 MEK 抑制剂的有限反应提供了新的解释。此外，ISGs的高表达与结直肠癌患者的生存率显着降低相关。令人兴奋的是，我们发现了新的治疗机会来克服结直肠癌中对 MEK 抑制的内在和获得性耐药性。