Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cell. 2018 Feb 8;172(4):857-868.e15. doi: 10.1016/j.cell.2017.12.020. Epub 2018 Jan 11.
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, 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.
野生型 KRAS 等位基因通过何种机制对各种癌症中的致癌 KRAS 产生生长抑制作用，包括肺腺癌（LUAD），目前尚不清楚。在这里，我们使用一种基因诱导的 KRAS 杂合性丢失（LOH）模型，表明 KRAS 二聚化介导野生型 KRAS 依赖的人源和鼠源 KRAS 突变 LUAD 肿瘤细胞的适应性，并导致对 MEK 抑制的耐药性。当野生型 KRAS 被 KRAS 取代时，这些效应被消除，KRAS 是一种突变体，它在不改变 KRAS 其他基本生化特性的情况下破坏 α4-α5 KRAS 二聚体界面处的二聚化，无论是在体外还是体内。此外，二聚化在突变型 KRAS 的致癌活性中起着关键作用。我们的研究为 KRAS 二聚化的作用提供了机制和生物学见解，并强调了破坏二聚化作为 KRAS 突变型癌症的治疗策略的重要性。
