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.