Autophagy as a therapeutic target in pancreatic cancer.
Autophagy as a therapeutic target in pancreatic cancer.
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DOI：
10.1038/s41416-020-01039-5
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发表时间：
2021-01
影响因子：
8.8
通讯作者：
Cassier PA
中科院分区：
文献类型：
--
作者：
Piffoux M;Eriau E;Cassier PA
胰腺导管腺癌（Pancreatic ductal adenocarcinoma， PDAC）的特点是早期转移和对抗癌治疗的抵抗，导致整体预后不良。尽管持续的研究努力，尚未有靶向治疗在PDAC中显示出有意义的疗效；癌基因KRAS和肿瘤抑制因子TP53的突变是PDAC中最常见的基因组改变，迄今为止临床可操作性较差。自噬是一个保守的过程，允许细胞回收改变或未使用的细胞器和细胞成分，已被证明在PDAC中上调，并涉及对细胞毒性化疗和靶向治疗的抗性。因此，自噬被认为是PDAC和其他癌症的潜在治疗靶点。尽管PDAC中自噬激活的分子机制才刚刚开始出现，但一些研究小组在PDAC和其他kras驱动的癌症模型中，将细胞外信号调节激酶/丝裂原活化蛋白激酶途径的抑制剂与自噬抑制剂结合使用时，已经报告了有趣的结果。在这篇文章中，我们回顾了关于自噬在PDAC中的作用的现有临床前数据，以及在这种癌症中调节自噬的药物的相关临床试验结果。
Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.
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