Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cancer Cell. 2014 Feb 10;25(2):243-56. doi: 10.1016/j.ccr.2014.01.005.
Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents in vitro and in vivo.
KRAS 突变在人类癌症中普遍存在，并且普遍预测对抗癌治疗的耐药性。尽管人们普遍认为获得激活突变赋予 RAS 基因功能自主性，但最近的研究表明，野生型 Ras 可能有助于突变 Ras 驱动的肿瘤发生。在这里，我们表明，在突变 K-Ras 癌细胞中下调野生型 H-Ras 或 N-Ras 会导致 Erk/p90RSK 和 PI3K/Akt 途径的过度激活，并且，Chk1 在抑制性位点 Ser 280 处的磷酸化。由此抑制 ATR/Chk1 信号传导会破坏 G2 DNA 损伤检查点的激活，并使突变 K-Ras 癌细胞对体外和体内 DNA 损伤化学治疗剂产生特异性敏感性。
