靶向RhoGTPase/ROCK信号通路治疗VHL/HIF信号通路驱动的癌症。
Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers.
作者信息
Thompson Jordan M, Landman Jaime, Razorenova Olga V
机构信息
Molecular Biology and Biochemistry Department, University of California Irvine, Irvine, CA, USA.
Urology Department, School of Medicine, University of California Irvine, Irvine, CA, USA.
出版信息
Small GTPases. 2020 Jan;11(1):32-38. doi: 10.1080/21541248.2017.1336193. Epub 2017 Jul 7.
The loss of the von Hippel-Lindau () tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. We recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation. Increased expression and activity of both HIFs and ROCK1 occurs in many types of cancer supporting the potential therapeutic role of ROCK inhibitors beyond CC-RCC. We also discuss future research required to establish prognostic markers to predict tumor response to ROCK inhibitors.
冯·希佩尔-林道（VHL）肿瘤抑制因子的缺失是透明细胞肾细胞癌（CC-RCC）的主要驱动因素，导致缺氧诱导因子（HIFs）的稳定和过度激活。ROCK1是一种著名的蛋白丝氨酸/苏氨酸激酶，被认为在癌症中发挥作用，包括细胞运动、转移和血管生成的改变。我们最近研究并确定了CC-RCC中VHL缺失与ROCK1抑制之间的合成致死相互作用，这种相互作用依赖于HIF的过度激活。HIFs和ROCK1的表达及活性增加在多种癌症中都有发生，这支持了ROCK抑制剂在CC-RCC之外的潜在治疗作用。我们还讨论了建立预后标志物以预测肿瘤对ROCK抑制剂反应所需的未来研究。
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