Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer.

Niranjan Awasthi,Roderich E Schwarz,Alexis Stefaniak,Margaret A Schwarz,Sheena Monahan

doi:10.18632/oncotarget.23684

Abstract

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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the US [1]
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 pancreatic ductal adenocarcinoma (PDAC) patients
In an AsPC-1 subcutaneous xenograft model, nabpaclitaxel alone, nab-paclitaxel plus gemcitabine and trametinib alone caused an inhibition in tumor growth while trametinib combination with chemotherapy regimens had a trend for additive effects (Figure 1A)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the US [1]. The 5-year survival rate in PDAC patients remains about 6% and the poor prognosis is attributed to several factors including late-stage diagnosis, an aggressive progression of the disease and high resistance to conventional therapies. FOLFIRINOX is a combination chemotherapy regimen that increased the median survival of unresectable PDAC patients to approximately 11 months. This regimen has a high toxicity potential, limiting its use to only patients with good performance status [5]. Nab-paclitaxel combined with gemcitabine has recently become the standard treatment for unresectable PDAC after demonstrating a 1.8 months improvement in patient survival compared to gemcitabine monotherapy [7]. Due to the limited clinical efficacy of current cytotoxic chemotherapy regimens for PDAC patients, novel therapeutic approaches are urgently needed to further improve patient survival

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