Abstract
Gemcitabine, a nucleoside analogue, is an important treatment for locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC) but provides only modest survival benefit. Targeting downstream effectors of the RAS/ERK signaling pathway by direct inhibition of MEK1/2 proteins is a promising therapeutic strategy, as aberrant activation of this pathway occurs frequently in PDAC. In this study, the ability of pimasertib, a selective allosteric MEK1/2 inhibitor, to enhance gemcitabine efficacy was tested and the molecular mechanism of their interaction was investigated. Cell survival and apoptosis were assessed by MTT and Caspase 3/7 Glo assays in human pancreatic cancer cell lines. Protein expression was detected by immunoblotting. The in vivo sensitivity of gemcitabine with pimasertib was evaluated in an orthotopic model of pancreatic tumor. Synergistic activity was observed when gemcitabine was combined sequentially with pimasertib, in human pancreatic cancer cells. In particular, pimasertib reduced ribonucleotide reductase subunit 1 (RRM1) protein, and this was associated with sensitivity to gemcitabine. Pretreatment with MG132 impaired reduction of RRM1 protein induced by pimasertib, suggesting that RRM1 is degraded posttranslationally. Immunoprecipitation indicated enhanced MDM2-mediated polyubiquitination of RRM1 through Lys-48-mediated linkage following pimasertib treatment, an effect mediated, in part, by AKT. Finally, the combination treatment with pimasertib and gemcitabine caused significant tumor growth delays in an orthotopic pancreatic cancer model, with RRM1 downregulation in pimasertib-treated mice. These results confirm an important role of RRM1 in gemcitabine response and indicate MEK as a potential target to sensitize gemcitabine therapy for PDAC. Clin Cancer Res; 21(24); 5563-77. ©2015 AACR.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease associated with poor prognosis, with few patients surviving 1 year after diagnosis [1]
These results confirm an important role of RRM1 in gemcitabine response and indicate mitogen-activated protein kinase (MEK) as a potential target to sensitize gemcitabine therapy for pancreatic ductal adenocarcinoma (PDAC)
The sensitivity to gemcitabine and the MEK1/2 inhibitor pimasertib on a panel of pancreatic cancer cell lines was measured by the MTT assay
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease associated with poor prognosis, with few patients surviving 1 year after diagnosis [1]. Gemcitabine, an antimetabolite with similar structure to the nucleoside cytidine, (Gem), (20,20difluorodeoxycytidine: dFdC) is an important chemotherapeutic agent for the treatment of locally advanced and metastatic PDAC, with benefit for only 25% of patients and with median survival of less than 6 months [2]. Among all gemcitabine-based combinations treatments tested in clinical trials, gemcitabine with abraxane, the albuminbound formulation of paclitaxel, has shown improved overall and progression-free survival in metastatic PDAC [4]. In a randomized phase III trial, the chemotherapy regimen FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) significantly prolonged median overall survival compared with gemcitabine monotherapy in patients with metastatic pancreatic cancer [5]
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