Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
Cancer Cell. 2011 Sep 13;20(3):400-13. doi: 10.1016/j.ccr.2011.08.014.
Ras-driven tumors are often refractory to conventional therapies. Here we identify a promising targeted therapeutic strategy for two Ras-driven cancers: Nf1-deficient malignancies and Kras/p53 mutant lung cancer. We show that agents that enhance proteotoxic stress, including the HSP90 inhibitor IPI-504, induce tumor regression in aggressive mouse models, but only when combined with rapamycin. These agents synergize by promoting irresolvable ER stress, resulting in catastrophic ER and mitochondrial damage. This process is fueled by oxidative stress, which is caused by IPI-504-dependent production of reactive oxygen species, and the rapamycin-dependent suppression of glutathione, an important endogenous antioxidant. Notably, the mechanism by which these agents cooperate reveals a therapeutic paradigm that can be expanded to develop additional combinations.
Ras 驱动的肿瘤通常对传统疗法有抗性。在这里，我们确定了一种有前途的针对两种 Ras 驱动的癌症的靶向治疗策略：NF1 缺陷性恶性肿瘤和 Kras/p53 突变型肺癌。我们表明，包括 HSP90 抑制剂 IPI-504 在内的增强蛋白毒性应激的药物在侵袭性小鼠模型中诱导肿瘤消退，但只有与雷帕霉素联合使用时才有效。这些药物通过促进无法解决的内质网应激而协同作用，导致内质网和线粒体灾难性损伤。这个过程由氧化应激驱动，氧化应激是由 IPI-504 依赖性产生的活性氧引起的，而雷帕霉素依赖性抑制谷胱甘肽，谷胱甘肽是一种重要的内源性抗氧化剂。值得注意的是，这些药物协同作用的机制揭示了一种治疗范例，可以扩展到开发其他组合。
