Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

中文翻译：

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克服对KRAS下游的双重先天免疫和MEK抑制的抵抗力。

尽管付出了巨大的努力，致癌性KRAS仍然对靶向治疗有抵抗力。结合的下游RAL-TBK1和MEK抑制作用仅在KRAS驱动的基因工程小鼠模型（GEMM）中诱导短暂的肺肿瘤缩小。使用敏感的KRAS; LKB1（KL）突变体背景，我们确定YAP1上调和治疗诱导的分泌组作为获得性耐药的介体。该程序是可逆的，与H3K27启动子乙酰化有关，并被BET抑制所抑制，使抗性KL细胞对TBK1 / MEK抑制重新敏感。YAP1组成型信号传导可促进KRAS; TP53（KP）突变型肺癌的内在抗性。因此，用BET抑制剂JQ1进行间歇性治疗可以克服KL和KP GEMM中联合途径抑制的耐药性。