Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, 30322, USA.
Institute for Systems Biology, Seattle, WA, 98109, USA.
Mol Cancer. 2019 Apr 10;18(1):85. doi: 10.1186/s12943-019-1012-4.
Lung cancer patients with KRAS mutation(s) have a poor prognosis due in part to the development of resistance to currently available therapeutic interventions. Development of a new class of anticancer agents that directly targets KRAS may provide a more attractive option for the treatment of KRAS-mutant lung cancer.
Here we identified a small molecule KRAS agonist, KRA-533, that binds the GTP/GDP-binding pocket of KRAS. In vitro GDP/GTP exchange assay reveals that KRA-533 activates KRAS by preventing the cleavage of GTP into GDP, leading to the accumulation of GTP-KRAS, an active form of KRAS. Treatment of human lung cancer cells with KRA-533 resulted in increased KRAS activity and suppression of cell growth. Lung cancer cell lines with KRAS mutation were relatively more sensitive to KRA-533 than cell lines without KRAS mutation. Mutating one of the hydrogen-bonds among the KRA-533 binding amino acids in KRAS (mutant K117A) resulted in failure of KRAS to bind KRA-533. KRA-533 had no effect on the activity of K117A mutant KRAS, suggesting that KRA-533 binding to K117 is required for KRA-533 to enhance KRAS activity. Intriguingly, KRA-533-mediated KRAS activation not only promoted apoptosis but also autophagic cell death. In mutant KRAS lung cancer xenografts and genetically engineered mutant KRAS-driven lung cancer models, KRA-533 suppressed malignant growth without significant toxicity to normal tissues.
The development of this KRAS agonist as a new class of anticancer drug offers a potentially effective strategy for the treatment of lung cancer with KRAS mutation and/or mutant KRAS-driven lung cancer.
KRAS 突变的肺癌患者预后较差，部分原因是对现有治疗干预措施产生耐药性。开发一类直接针对 KRAS 的新型抗癌药物可能为治疗 KRAS 突变型肺癌提供更有吸引力的选择。
在这里，我们鉴定了一种小分子 KRAS 激动剂 KRA-533，它能与 KRAS 的 GTP/GDP 结合口袋结合。体外 GDP/GTP 交换试验表明，KRA-533 通过阻止 GTP 裂解为 GDP 来激活 KRAS，导致 GTP-KRAS 的积累，即 KRAS 的一种活性形式。用 KRA-533 处理人肺癌细胞会导致 KRAS 活性增加和细胞生长抑制。具有 KRAS 突变的肺癌细胞系比没有 KRAS 突变的细胞系对 KRA-533 更为敏感。在 KRAS 中使 KRA-533 结合的氨基酸之一（突变 K117A）的氢键之一突变会导致 KRAS 无法与 KRA-533 结合。KRA-533 对 K117A 突变 KRAS 的活性没有影响，表明 KRA-533 与 K117 的结合对于 KRA-533 增强 KRAS 活性是必需的。有趣的是，KRA-533 介导的 KRAS 激活不仅促进了细胞凋亡，还促进了自噬性细胞死亡。在突变 KRAS 肺癌异种移植瘤和基因工程突变 KRAS 驱动的肺癌模型中，KRA-533 抑制了恶性生长，而对正常组织没有明显的毒性。
作为一类新型抗癌药物，这种 KRAS 激动剂的开发为治疗 KRAS 突变和/或突变 KRAS 驱动的肺癌提供了一种潜在有效的策略。
