Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
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DOI：
10.1038/s41388-018-0554-z
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Whittaker SR
中科院分区：
文献类型：
--
作者：
Wagner S;Vlachogiannis G;De Haven Brandon A;Valenti M;Box G;Jenkins L;Mancusi C;Self A;Manodoro F;Assiotis I;Robinson P;Chauhan R;Rust AG;Matthews N;Eason K;Khan K;Starling N;Cunningham D;Sadanandam A;Isacke CM;Kirkin V;Valeri N;Whittaker SR
尽管在BRAF突变型黑色素瘤中显示出临床活性，但MEK抑制剂（MEKi）曲美替尼未能在KRAS突变型结直肠癌中显示出临床益处。为了确定耐MEKi的机制，我们采用了MEKi敏感与MEKi耐药结直肠癌细胞系的药物基因组学分析。引人注目的是，干扰素和炎症相关的基因集富集在细胞系表现出内在的和获得性的MEK抑制抗性。布罗莫结构域抑制剂JQ1抑制干扰素刺激基因（ISG）的表达，并与MEK抑制剂组合显示协同作用，并诱导MEKi耐药结直肠癌细胞系的凋亡。ISG表达在患者来源的类器官模型中得到证实，这些模型显示出对曲美替尼的耐药性，并通过JQ1共同治疗重新敏感。在结直肠癌的体内模型中，联合治疗显著抑制肿瘤生长。我们的研究结果为KRAS突变型结直肠癌对MEK抑制剂的有限反应提供了新的解释，KRAS突变型结直肠癌以其炎症性质而闻名。此外，ISGs的高表达与结直肠癌患者的生存率显著降低相关。令人兴奋的是，我们已经确定了新的治疗机会，以克服结肠直肠癌中对MEK抑制的内在和获得性抗性。
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.
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