Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Cell Rep. 2018 Feb 13;22(7):1889-1902. doi: 10.1016/j.celrep.2018.01.051.
KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.
KRAS 可以结合许多效应蛋白，这些蛋白会激活不同的下游信号事件。最著名的是 RAF、磷脂酰肌醇（PI）-3'激酶和 RalGDS 家族，但也有许多其他直接和间接的效应物被报道。我们使用一种组合型 siRNA 阵列筛选方法，在 92 个细胞系中敲低了 41 个 KRAS 效应物节点，以定量的方式评估了这些效应物对几种主要表型的贡献。我们表明，每种细胞系都有独特的效应物依赖性组合，但尽管存在这种异质性，我们仍能够鉴定出两种主要的肺、胰腺和大肠 KRAS 突变型癌症亚型，这反映了不同的 KRAS 效应物结合和治疗干预的机会。
