Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer.
Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer.
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KRAS 突变胰腺癌中 RAS 下游信号传导和表观遗传通路的协同阻断
DOI：
10.18632/aging.204031
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发表时间：
2022-04-25
期刊：
影响因子：
5.2
通讯作者：
Wang, Liwei
中科院分区：
文献类型：
--
作者：
Zhang, Xiaofei;Mao, Tiebo;Xu, Haiyan;Li, Shumin;Yue, Ming;Ma, Jingyu;Yao, Jiayu;Wang, Yongchao;Zhang, Xiao;Ge, Weiyu;Wang, Yanling;Shentu, Daiyuan;Wang, Liwei
背景：胰腺导管腺癌（PDAC）是一种高致死性恶性肿瘤，缺乏有效的治疗靶点。曲美替尼被认为是PDAC中有前途的潜在间接靶向KRAS抑制剂。然而，临床结果很差。JQ 1与化疗或潜在的靶向治疗胰腺癌时显示出显着的协同作用。曲美替尼和JQ 1联合治疗对PDAC的影响仍有待充分阐明。方法：观察曲美替尼和JQ 1对7株KRAS突变胰腺癌细胞株的增殖抑制作用和细胞毒作用。使用发光细胞活力测定评价药物单独或组合的细胞毒性作用。进行免疫印迹分析以研究p62和自噬的变化。结果如下：我们发现，无论是曲美替尼或JQ 1单独抑制一些胰腺癌细胞系与KRAS改变的增殖，无论KRAS的突变位点和其他驱动基因的异常状态。在曲美替尼耐药细胞和曲美替尼敏感细胞中均观察到曲美替尼和JQ 1联合治疗的协同效应。在曲美替尼敏感的PDAC细胞中，与曲美替尼单独治疗相比，联合治疗明确抑制了p62表达，而高水平的LC 3表达变化不大。在曲美替尼耐药的PDAC细胞中，与单一药物相比，MEK/BET抑制剂组合显著降低p62表达，而加入抗自噬治疗后p62表达增加。结论：阻断RAS下游信号传导和表观遗传途径协同增加KRAS突变PDAC细胞中的抗增殖活性。联合治疗协同作用可在不同胰腺癌亚型中诱导不同的细胞死亡模式。
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy and lacks effective therapeutic targets. Trametinib is considered to be a promising potential indirectly targeted KRAS inhibitor in PDAC. However, the clinical outcomes were poor. JQ1 displayed a significant synergistic effect when combined with chemotherapy or potential targeted therapy in pancreatic cancer. The impact of Trametinib and JQ1 combination treatment in PDAC remains to be fully elucidated. Methods: The efficacy of trametinib and JQ1 on cell proliferation and cytotoxicity was assayed in 7 KRAS mutant pancreatic cancer cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using a luminescent cell viability assay. Immunoblot analysis was carried out to investigate changes in p62 and autophagy. Results: We found that either trametinib or JQ1 alone inhibited the proliferation of some pancreatic cancer cell lines with KRAS alterations, irrespective of the mutational loci of KRAS and the aberrant status of the other driver genes. The synergistic effects of combination treatment of trametinib and JQ1 were observed in both trametinib-resistant and trametinib-sensitive cells. In trametinib-sensitive PDAC cells, the combined treatment definitely inhibited p62 expression compared with trametinib alone, while LC3 expression at high levels changed little. In trametinib-resistant PDAC cells, the combination of MEK/BET inhibitor dramatically decreased p62 expression compared with single agent, while p62 expression increased after anti-autophagic therapy was added. Conclusions: Blocking RAS downstream signaling and epigenetic pathway synergistically increases the antiproliferative activity in KRAS mutant PDAC cells. Combination therapeutic synergism may induce different cell death modes in different pancreatic cancer subtypes.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
50.3
作者：
Guerra, Stephanie L.;Maertens, Ophelia;Cichowski, Karen
通讯作者：
Cichowski, Karen
影响因子：
8.8
作者：
Piffoux M;Eriau E;Cassier PA
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Cassier PA
DOI：
10.1016/j.annonc.2020.11.013
发表时间：
2021-03
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Casolino R;Braconi C;Malleo G;Paiella S;Bassi C;Milella M;Dreyer SB;Froeling FEM;Chang DK;Biankin AV;Golan T
通讯作者：
Golan T
影响因子：
51.1
作者：
Infante, Jeffrey R.;Fecher, Leslie A.;Messersmith, Wells A.
通讯作者：
Messersmith, Wells A.