Purpose: Despite the challenge to directly target mutant KRAS due to its high GTP affinity, some agents are under development against downstream signaling pathways, such as MEK inhibitors. However, it remains controversial whether MEK inhibitors can boost current chemotherapy in KRAS-mutant lung tumors in clinic. Considering the genomic heterogeneity among patients with lung cancer, it is valuable to test potential therapeutics in KRAS mutation-driven mouse models.Experimental Design: We first compared the pERK1/2 level in lung cancer samples with different KRAS substitutions and generated a new genetically engineered mouse model whose tumor was driven by KRAS G12C, the most common KRAS mutation in lung cancer. Next, we evaluated the efficacy of selumetinib or its combination with chemotherapy, in KRASG12C tumors compared with KRASG12D tumors. Moreover, we generated KRASG12C/p53R270H model to explore the role of a dominant negative p53 mutation detected in patients in responsiveness to MEK inhibition.Results: We determined higher pERK1/2 in KRASG12C lung tumors compared with KRASG12D Using mouse models, we further identified that KRASG12C tumors are significantly more sensitive to selumetinib compared with KrasG12D tumors. MEK inhibition significantly increased chemotherapeutic efficacy and progression-free survival of KRASG12C mice. Interestingly, p53 co-mutation rendered KRASG12C lung tumors less sensitive to combination treatment with selumetinib and chemotherapy.Conclusions: Our data demonstrate that unique KRAS mutations and concurrent mutations in tumor-suppressor genes are important factors for lung tumor responses to MEK inhibitor. Our preclinical study supports further clinical evaluation of combined MEK inhibition and chemotherapy for lung cancer patients harboring KRAS G12C and wild-type p53 status. Clin Cancer Res; 24(19); 4854-64. ©2018 AACR.

中文翻译：

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评估 KRASG12C 驱动的肺癌小鼠模型中 MEK 抑制的治疗效果。

目的：尽管由于其高 GTP 亲和力而直接靶向突变 KRAS 存在挑战，但一些针对下游信号通路的药物正在开发中，例如 MEK 抑制剂。然而，MEK抑制剂是否能促进目前临床上KRAS突变肺肿瘤的化疗仍存在争议。考虑到肺癌患者的基因组异质性，在 KRAS 突变驱动的小鼠模型中测试潜在的治疗方法是有价值的。 实验设计：我们首先比较了具有不同 KRAS 取代的肺癌样本中的 pERK1/2 水平，并生成了新的基因工程其肿瘤由 KRAS G12C（肺癌中最常见的 KRAS 突变）驱动的小鼠模型。接下来，我们与 KRASG12D 肿瘤相比，评估了司美替尼或其联合化疗在 KRASG12C 肿瘤中的疗效。此外，我们生成了 KRASG12C/p53R270H 模型，以探讨患者中检测到的显性失活 p53 突变在 MEK 抑制反应中的作用。结果：与 KRASG12D 相比，我们确定 KRASG12C 肺部肿瘤中的 pERK1/2 更高。使用小鼠模型，我们进一步确定：与 KrasG12D 肿瘤相比，KRASG12C 肿瘤对司美替尼更加敏感。MEK 抑制显着提高了 KRASG12C 小鼠的化疗效果和无进展生存期。有趣的是，p53 共突变使 KRASG12C 肺肿瘤对司美替尼和化疗联合治疗的敏感性降低。结论：我们的数据表明，独特的 KRAS 突变和肿瘤抑制基因中的并发突变是肺肿瘤对 MEK 抑制剂反应的重要因素。我们的临床前研究支持对携带 KRAS G12C 和野生型 p53 状态的肺癌患者进行 MEK 抑制和化疗联合的进一步临床评估。临床癌症研究；24（19）；4854-64。©2018 AACR。