Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer
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Niranjan Awasthi1,4, Sheena Monahan1, Alexis Stefaniak2, Margaret A. Schwarz3,4 and Roderich E. Schwarz1,5
1Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46617, USA
3Department of Pediatrics, Indiana University School of Medicine, South Bend, IN 46617, USA
4Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46617, USA
5Goshen Center for Cancer Care, Goshen, IN 46526, USA
Niranjan Awasthi, email: [email protected]
Keywords: pancreatic cancer; nab-paclitaxel; trametinib; MEK inhibitor; combination therapy
Received: April 13, 2017 Accepted: December 19, 2017 Published: December 25, 2017
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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