Oncogenic KRAS signalling in pancreatic cancer.
Oncogenic KRAS signalling in pancreatic cancer.
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DOI：
10.1038/bjc.2014.215
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发表时间：
2014-08-26
影响因子：
8.8
通讯作者：
Saur, D.
中科院分区：
文献类型：
--
作者：
Eser, S.;Schnieke, A.;Schneider, G.;Saur, D.
关键词：
胰腺导管腺癌（PDAC）几乎是普遍致命的。尽管进行了最大程度的治疗，但每年的死亡人数与新诊断病例数相等。在过去的30年里，尽管在临床前和临床科学方面做出了巨大的努力，但总体5年生存率<5%仍然顽固地保持不变。毫无疑问，迫切需要进一步提高我们对胰腺癌生物学、治疗反应和复发的理解，并确定新的治疗靶点。该领域的严格研究已经发现了PDAC发展和进展过程中发生的遗传畸变。在大多数情况下，PDAC是由致癌突变KRAS启动的，这已被证明是胰腺肿瘤的驱动因素。然而，所有直接靶向KRAS的尝试在临床上都失败了，并且KRAS被广泛认为是不可用药的。这导致了大量的努力来识别由突变激活的KRAS编排的可药物化的关键下游靶标和节点。这包括背景特异性KRAS效应子途径、合成致死相互作用伴侣和KRAS驱动的代谢变化。在这里，我们回顾了致癌KRAS信号转导的最新进展，并讨论了这些可能有利于未来的PDAC治疗。
Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.
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通讯作者：
McMahon M
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
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通讯作者：
Grimmond, Sean M.