Awasthi Niranjan, Monahan Sheena, Stefaniak Alexis, Schwarz Margaret A, Schwarz Roderich E
Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA.
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA.
Oncotarget. 2017 Dec 25;9(4):5274-5286. doi: 10.18632/oncotarget.23684. eCollection 2018 Jan 12.
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.
纳米白蛋白结合型紫杉醇（NPT）联合吉西他滨（Gem）是胰腺导管腺癌（PDAC）的标准化疗方案。RAS/RAF/MEK/ERK（MAPK）信号通路的基因改变导致ERK级联反应的组成性激活，被认为是PDAC的驱动因素。抑制RAS-MAPK级联反应中的下游靶点，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MEK1/2激酶活性的小分子抑制剂）联合纳米白蛋白结合型紫杉醇化疗的疗效。在皮下AsPC-1和Panc-1 PDAC异种移植瘤模型中，在化疗方案中添加曲美替尼显示出对肿瘤生长抑制有相加作用的趋势。在腹膜播散模型中，与对照组（20天）相比，接受NPT治疗（33天，增加65%）、Tra治疗（31天，增加55%）、NPT+Tra治疗（37天，增加85%）、NPT+Gem治疗（39天，增加95%）和NPT+Gem+Tra治疗（49天，增加145%）后，动物中位生存期延长。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着磷酸化ERK的减少以及裂解的半胱天冬酶-3和裂解的PARP-1蛋白的增加。这些发现表明，通过特异性抑制MEK1/2激酶活性可以增强纳米白蛋白结合型紫杉醇化疗的效果，并支持曲美替尼联合标准化的纳米白蛋白结合型紫杉醇化疗在PDAC患者中的临床应用。
