The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRAS^D154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.

中文翻译：

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KRAS二聚化影响突变KRAS的MEK抑制剂敏感性和致癌活性。

人们对野生型KRAS等位基因在多种癌症（包括肺腺癌（LUAD））中对致癌性KRAS产生生长抑制作用的机制了解甚少。在这里，使用遗传诱导的KRAS杂合性丧失（LOH）的模型，我们显示KRAS二聚化介导了人和鼠KRAS突变体LUAD肿瘤细胞的野生型KRAS依赖性适应性，并对MEK抑制产生了抗性。将野生型KRAS替换为KRAS ^D154Q时，将消除这些影响，该突变体可破坏α4-α5KRAS二聚体界面的二聚化，而不会改变KRAS在体外和体内的其他基本生化特性。而且，二聚化在突变体KRAS的致癌活性中具有关键作用。我们的研究提供了有关KRAS二聚化作用的机制和生物学见解，并突出了二聚化破坏作为KRAS突变型癌症的治疗策略的作用。