Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy
Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapy
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DOI：
10.1172/jci.insight.129905
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发表时间：
2020-04-23
期刊：
影响因子：
8
通讯作者：
Yeh, Jen Jen
中科院分区：
文献类型：
--
作者：
Lipner, Matthew B.;Peng, Xianlu L.;Yeh, Jen Jen
在美国，每年有超过55,000人被诊断为胰腺导管腺癌（PDAC），其中不到20%的患者在诊断后存活一年。化疗在几乎所有PDAC病例中都被考虑或使用，但对这些常见治疗产生耐药性的复杂信号反应的了解有限。在这里，我们采用无偏倚的方法来研究患者源性异种移植（PDX） RAC模型化疗后蛋白激酶网络的变化，以促进合理药物组合的设计。化疗方案后的蛋白质组学分析显示，JNK-JUN信号的激活发生在5-氟尿嘧啶加亚叶酸钙（5-FU + LEU）和FOLFOX （5-FU + LEU加奥沙利铂[OX]）之后，而不是单独使用OX或吉西他滨之后。使用不可逆抑制剂INK-IN-8和基因操作进行的细胞和肿瘤生长试验表明，JNK和JUN分别有助于FOLFOX后的化疗耐药和癌细胞存活。活性JNK1和JUN与这些效应特别相关，与JNK-1N-8的协同作用与folfox介导的JUN激活、细胞周期失调和DNA损伤反应有关。这项研究强调了JNK-IN-8作为一种生物工具的潜力，以及与FOLFOX联合治疗PDAC的潜力，并强调了根据个体肿瘤的功能特征定制治疗的必要性。
Over 55,000 people in the United States are diagnosed with pancreatic ductal adenocarcinoma (PDAC) yearly, and fewer than 20% of these patients survive a year beyond diagnosis. Chemotherapies are considered or used in nearly every PDAC case, but there is limited understanding of the complex signaling responses underlying resistance to these common treatments. Here, we take an unbiased approach to study protein kinase network changes following chemotherapies in patient-derived xenograft (PDX) models of RAC to facilitate design of rational drug combinations. Proteomics profiling following chemotherapy regimens reveals that activation of JNK-JUN signaling occurs after 5-fluorouracil plus leucovorin (5-FU + LEU) and FOLFOX (5-FU + LEU plus oxaliplatin [OX]), but not after OX alone or gemcitabine. Cell and tumor growth assays with the irreversible inhibitor INK-IN-8 and genetic manipulations demonstrate that JNK and JUN each contribute to chemoresistance and cancer cell survival after FOLFOX. Active JNK1, and JUN are specifically implicated in these effects, and synergy with JNK-1N-8 is linked to FOLFOX-mediated JUN activation, cell cycle dysregulation, and DNA damage response. This study highlights the potential for JNK-IN-8 as a biological tool and potential combination therapy with FOLFOX in PDAC and reinforces the need to tailor treatment to functional characteristics of individual tumors.