Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer.
Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer.
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DOI：
10.18632/oncotarget.23684
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发表时间：
2018-01-12
期刊：
影响因子：
--
通讯作者：
Schwarz RE
中科院分区：
文献类型：
--
作者：
Awasthi N;Monahan S;Stefaniak A;Schwarz MA;Schwarz RE
白蛋白结合型紫杉醇（NPT）与吉西他滨（Gem）的组合代表了胰腺导管腺癌（PDAC）的标准化疗。RAS/RAF/MEK/ERK（MAPK）信号传导途径的遗传改变产生ERK级联的组成性激活，其被认为是PDAC的驱动因素。抑制RAS-MAPK级联中的下游靶标如MEK仍然是一种有前景的治疗策略。在PDAC的临床前模型中评估了曲美替尼（Tra）（一种MEK 1/2激酶活性的小分子抑制剂）与基于nab-紫杉醇的化疗组合的功效。在化疗方案中添加曲美替尼显示出对皮下AsPC-1和Panc-1 PDAC异种移植物中肿瘤生长抑制的累加效应趋势。在腹膜播散模型中，与对照组（20天）相比，在用NPT（33天，增加65%）、Tra（31天，增加55%）、NPT+Tra（37天，增加85%）、NPT+Gem（39天，增加95%）和NPT+Gem+Tra（49天，增加145%）治疗后，中值动物存活率增加。治疗对肿瘤内增殖和凋亡的影响与肿瘤生长抑制相对应。曲美替尼的作用特别伴随磷酸化ERK的减少和裂解的半胱天冬酶-3和PARP-1蛋白的增加。这些结果表明，nab-紫杉醇为基础的化疗的效果可以通过特异性抑制MEK 1/2激酶活性增强，并支持曲美替尼与标准的nab-紫杉醇为基础的化疗药物在PDAC患者的临床应用。
Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.
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影响因子：
3.7
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
通讯作者：
Maira SM
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
4.8
作者：
Lindberg, James M.;Newhook, Timothy E.;Adair, Sara J.;Walters, Dustin M.;Kim, Alison J.;Stelow, Edward B.;Parsons, J. Thomas;Bauer, Todd W.
通讯作者：
Bauer, Todd W.
DOI：
10.2147/dddt.s88023
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Kundranda MN;Niu J
通讯作者：
Niu J
影响因子：
3
作者：
Chen N;Brachmann C;Liu X;Pierce DW;Dey J;Kerwin WS;Li Y;Zhou S;Hou S;Carleton M;Klinghoffer RA;Palmisano M;Chopra R
通讯作者：
Chopra R