K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.
K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.
复制标题
DOI：
10.1371/journal.pone.0044146
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Maira SM
中科院分区：
文献类型：
--
作者：
Hofmann I;Weiss A;Elain G;Schwaederle M;Sterker D;Romanet V;Schmelzle T;Lai A;Brachmann SM;Bentires-Alj M;Roberts TM;Sellers WR;Hofmann F;Maira SM
激活K-RAS突变在胰腺癌中发生率为90%，迄今为止还没有针对该癌基因的治疗方法。K-RAS信号通过下游效应通路，如MAPK和PI3K信号通路，并且很多努力都集中在开发针对这些通路成分的药物上。为了更好地了解K-RAS及其下游信号通路MAPK和PI3K在胰腺肿瘤维持中的需求，我们建立了一个诱导的K-RAS敲低系统，使我们能够在已建立的肿瘤中消融K-RAS。在所有胰腺异种移植模型中，敲低K-RAS导致肿瘤生长受损，这表明K-RAS表达确实是K-RAS突变胰腺肿瘤维持所必需的。我们进一步研究了K-RAS下游的信号传导，发现K-RAS敲除后pERK水平显著降低。相比之下，由于几乎无法检测到基础表达水平，因此没有观察到对pAKT水平的影响。为了研究MAPK和PI3K通路对肿瘤维持的要求，我们测试了三种选择的胰腺异种移植模型对MEK或PI3K抑制的反应。三种模型的肿瘤对MEK抑制均有回归，但对PI3K抑制的反应不明显。联合应用PI3K抑制剂可进一步增强MEK对胰腺异种移植物的抑制作用。这些数据为在含有K-RAS突变的胰腺癌患者群体的临床试验中检测MEK和PI3K抑制剂的组合提供了进一步的理论依据。
Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.
登录
查看更多内容
影响因子：
--
作者：
Jiang, Bing-Hua;Liu, Ling-Zhi
通讯作者：
Liu, Ling-Zhi
影响因子：
3.8
作者：
Chang Q;Chapman MS;Miner JN;Hedley DW
通讯作者：
Hedley DW
DOI：
10.1158/1541-7786.mcr-08-0577
发表时间：
2009-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Matsuo Y;Campbell PM;Brekken RA;Sung B;Ouellette MM;Fleming JB;Aggarwal BB;Der CJ;Guha S
通讯作者：
Guha S
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
120.1
作者：
Chan, Denise A.;Giaccia, Amato J.
通讯作者：
Giaccia, Amato J.