Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.
Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.
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DOI：
10.1158/2159-8290.cd-14-0362
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发表时间：
2014-08
期刊：
影响因子：
28.2
通讯作者：
Kimmelman AC
中科院分区：
文献类型：
--
作者：
Yang A;Rajeshkumar NV;Wang X;Yabuuchi S;Alexander BM;Chu GC;Von Hoff DD;Maitra A;Kimmelman AC
胰腺导管腺癌对现有的治疗方法难以奏效。我们之前已经证明，这些肿瘤的自噬增加，抑制自噬会导致肿瘤生长减少。利用由致癌基因Kras和p53的随机杂合性缺失驱动的胰腺癌的本土模型，我们证明了虽然胰腺自噬的遗传消融导致肿瘤起源的增加，但这些癌前病变发展为侵袭性癌症的能力受到损害，从而导致生存时间延长。此外，具有不同P53状态的小鼠胰腺癌细胞系对自噬的药物和遗传抑制都很敏感。最后，一项使用羟基氯喹治疗的具有遗传特征的患者来源的异种移植物的小鼠临床前试验显示，在所有肿瘤集合中都有反应。总之，我们的数据支持自噬在胰腺癌中的关键作用，抑制自噬可能在这些癌症的治疗中具有临床实用价值，与P53状态无关。
Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of p53, we demonstrate that while genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. Additionally, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Lastly, a mouse pre-clinical trial using cohorts of genetically characterized patient derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together our data support the critical role of autophagy in pancreatic cancer and that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.