Assessing Therapeutic Efficacy of MEK Inhibition in a KRAS(G12C)-Driven Mouse Model of Lung Cancer.
Assessing Therapeutic Efficacy of MEK Inhibition in a KRAS(G12C)-Driven Mouse Model of Lung Cancer.
复制标题
评估MEK抑制在KRAS（G12C）驱动的肺癌模型中的治疗功效。
DOI：
10.1158/1078-0432.ccr-17-3438
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发表时间：
2018-10-01
期刊：
影响因子：
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通讯作者：
Wong KK
中科院分区：
文献类型：
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作者：
Li S;Liu S;Deng J;Akbay EA;Hai J;Ambrogio C;Zhang L;Zhou F;Jenkins RW;Adeegbe DO;Gao P;Wang X;Paweletz CP;Herter-Sprie GS;Chen T;Gutiérrez-Quiceno L;Zhang Y;Merlino AA;Quinn MM;Zeng Y;Yu X;Liu Y;Fan L;Aguirre AJ;Barbie DA;Yi X;Wong KK
尽管由于其高GTP亲和力而直接靶向突变型KRAS存在挑战，但一些针对下游信号传导途径的药物正在开发中，例如MEK抑制剂。然而，MEK抑制剂在临床上是否能增强KRAS突变型肺癌的现有化疗效果仍存在争议。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。我们首先比较了具有不同KRAS取代的肺癌样本中的pERK 12水平，并生成了一种新的基因工程小鼠模型，其肿瘤由肺癌中最常见的KRAS突变KRASG 12 C驱动。接下来，我们评估了司美替尼或其与化疗的组合在KRASG 12 C肿瘤中与KRASG 12 D肿瘤相比的疗效。此外，我们建立了KRASG 12 C/p53 R270 H模型，以探讨在患者中检测到的显性负性p53突变在对MEK抑制的反应性中的作用。我们在KRASG 12 C肺肿瘤中确定了比KRASG 12 D更高的pERK 12。使用小鼠模型，我们进一步确定了与KrasG 12 D肿瘤相比，KRASG 12 C肿瘤对司美替尼显著更敏感。MEK抑制显著增加KRASG 12 C小鼠的化疗功效和无进展存活。有趣的是，p53共突变使KRASG 12 C肺肿瘤对司美替尼和化疗的联合治疗不太敏感。我们的数据表明，独特的KRAS突变和肿瘤抑制基因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KRASG 12 C和野生型p53状态的肺癌患者联合MEK抑制和化疗的进一步临床评价。
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. 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 KRASG12C, 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. 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. 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 KRASG12C and wild-type p53 status.