Vena, F; (2016) MEK inhibition in pancreas cancer. Doctoral thesis , UCL (University College London).

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is resistant to chemotherapy. Gemcitabine, a nucleoside analogue, is an important component of treatment for locally advanced and metastatic PDAC, but provides only modest survival benefit. The enzyme Ribonucleotide Reductase (RR) catalyses the conversion of ribonucleotides into deoxyribonucleotides, required for DNA synthesis and repair. Several studies have demonstrated that RR large subunit-1 (RRM1) is associated with gemcitabine resistance in PDAC. The RAS/RAF/MEK/ERK signalling pathways regulates cellular proliferation, differentiation and survival. Targeting downstream effectors of the RAS gene by direct inhibition of MEK (MAPKK) proteins is a rational therapeutic strategy, since aberrant activation of this pathway occurs frequently in PDAC. In this study, the ability of pimasertib (AS703026), a highly selective and allosteric MEK1/2 inhibitor, to enhance gemcitabine efficacy was tested and the molecular mechanism of their interaction was investigated. Synergistic antiproliferative effects and increased apoptosis were observed when pimasertib was combined sequentially with gemcitabine in human pancreatic cancer cells. Importantly, pimasertib reduced the expression of RRM1 protein and this was associated with sensitivity to gemcitabine. Pre-treatment with the proteasome inhibitor MG132 impaired RRM1 downregulation induced by pimasertib, suggesting RRM1 is degraded through the ubiquitin-proteasome system. Immunoprecipitation experiments indicated enhanced MDM2-mediated polyubiquitination of RRM1 through lys48-mediated linkage following pimasertib treatment, an effect in part mediated by AKT. Finally, the combination treatment of pimasertib with gemcitabine caused significant tumor growth delay in an orthotopic pancreatic cancer model, with RRM1 downregulation in pimasertib-treated mice. These results indicate MEK as a potential target to sensitize gemcitabine therapy through modulation of RRM1 protein stability and underline the importance of drug scheduling in achieving efficacious antitumor activity. This study has provided mechanistic insights to the synergistic interaction between gemcitabine and pimasertib that could be further investigated in design of future clinical trials.

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