Abstract 4202: Trametinib, a MEK inhibitor, augments nab-paclitaxel based chemotherapy response in preclinical models of pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer related deaths in the USA with a 5-year survival less than 6%. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, NPT) has demonstrated 8.5 months median survival in combination with gemcitabine, and now represents a standard of care for PDAC patients. Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated in many human cancers. In PDAC, activating K-ras mutations occur at a frequency of 90%, rendering this a potential therapeutic target. Efforts to develop drugs that directly target mutant KRAS protein remain challenging due to target specificity issues. Alternative strategies therefore focus towards inhibition of downstream targets in the RAS-MAPK cascade such as MEK. Trametinib (Tra) is a potent and highly selective small molecule inhibitor of MEK1/2 kinase activity. We evaluated efficacy of trametinib to enhance antitumor response of nab-paclitaxel based chemotherapy regimens in preclinical models of PDAC using K-ras mutant cell lines. In subcutaneous PDAC xenografts using AsPC-1 cells, net tumor growth in different therapy groups was 432.6 mm3 in controls, 105.3 mm3 after NPT (p=0.0023), 184 mm3 after Tra (p=0.0018), 81 mm3 after NPT+Tra (p=0.0003), 37.3 mm3 after NPT+Gem (p=0.0025) and -8.1 mm3 (tumor regression) after NPT+Gem+Tra (p<0.0001). In another subcutaneous PDAC xenografts using Panc-1 cells, net tumor growth in different therapy groups was: 274.1 mm3 in controls, 80.8 mm3 after NPT (p=0.0002), 150.6 mm3 after Tra (p=0.0047), 75.1 mm3 after NPT+Tra (p=0.0002), 48.4 mm3 after NPT+Gem (p=0.0004) and 3.8 mm3 after NPT+Gem+Tra (p<0.0001). In PDAC peritoneal dissemination model using AsPC-1 cells, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase, p=0.0004), Tra (31 days, a 55% increase, p=0.0004), NPT+Tra (37 days, a 85% increase, p=0.0001), NPT+Gem (39 days, a 95% increase, p=0.0001) and NPT+Gem+Tra (49 days, a 145% increase, p<0.0001). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. In vitro studies demonstrated inhibition in PDAC cell (AsPC-1, Panc-1, Mia PaCa-2, CFPAC) proliferation by NPT+Gem, Tra, and combination. Immunoblot analysis revealed that trametinib effects were specifically accompanied by decrease in phospho-ERK expression and increase in the expression of apoptosis-related cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel based chemotherapy regimens can be enhanced through specific inhibition of MEK1/2 kinase activity, which clinically could lead to improved PDAC therapy effects. Citation Format: Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret A. Schwarz, Roderich E. Schwarz. Trametinib, a MEK inhibitor, augments nab-paclitaxel based chemotherapy response in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4202. doi:10.1158/1538-7445.AM2017-4202