Background: Intense efforts to improve current molecular therapy in pancreatic ductal adenocarcinoma (PDAC) have focused on suppression of the MAPK/ERK1/2 pathway. Inhibitors of MEK1/2, downstream target of the frequently mutated RAS oncogene, are currently in development. Recently, results of a phase II clinical trial revealed that selumetinib, a second-generation MEK1/2 inhibitor, has not yielded its promising preclinical efficacy in PDAC patients. A novel Extracellular Signal Regulated Kinase 1/2 (ERK1/2) inhibitor, VTX-11e, has been recently developed as a potent and selective inhibitor of ERK1/2. In this study, we evaluated the effects of VTX-11e on cell growth and apoptosis in pancreatic cancer cell lines and compared VTX-11e to selumetinib.

Methods: Fifty percent Growth Inhibition (GI50) and Lethal Dose (LD) were determined at 72 hours in 65 PDAC cell lines with increasing concentrations of VTX-11e or selumetinib. Apoptosis was quantified by Annexin V/PI following VTX-11e or selumetinib treatment at increasing concentrations at 24 and 72 hours and 7 days. Elk1 phosphorylation levels were determined by Western Blotting as a well-established readout for downstream MAPK pathway output.

Results: More than a third of VTX-11e-treated PDAC lines showed GI50 concentrations of ≤2μM. LD drug response curves of cell lines treated with VTX-11e showed cell death induction at lower concentrations than selumetinib in close to half the cell lines tested. This finding was confirmed by assessment of apoptosis by the AnnexinV/PI assay. We demonstrated that VTX-11e induced significant increased apoptosis in a subset of the PDAC lines compared to selumetinib, leading to as much as 50% apoptotic cells. Furthermore, VTX-11e and selumetinib suppressed phosphorylation of downstream target Elk1 equally.

Conclusion: Our results show that the novel ERK1/2 inhibitor VTX-11e leads to a significant increase in apoptosis as compared to the MEK1/2 inhibitor selumetinib in a subset of pancreatic cancer cell lines. This finding suggests that targeting ERK1/2 directly may be a more effective therapeutic strategy than targeting upstream MEK1/2 in some PDAC. Current studies are ongoing to determine the differential mechanism of action between VTX-11e and selumetinib.

Citation Format: Anne M. Miermont, Holger Pflicke, Hannah Guan, Harshini Chinnasamy, Craig Thomas, Udo Rudloff. Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5538. doi:10.1158/1538-7445.AM2013-5538