Erk Inhibition As A Therapeutic Option For The Treatment Of Raf- And Mek-Inhibitor Resistant Tumors

The MAPK pathway represents a prime target for therapeutic intervention in cancer. Recent approvals of B-Raf and Mek inhibitors lead to exciting antitumor activities and survival benefits. However the observation of resistance to such Raf and Mek inhibitors has been documented in both clinical and preclinical trials. These phenomena stimulated further research into the regulation of the MAPK pathway and led to the suggestion to target the downstream kinase Erk, as well as to combine its targeting with Raf and Mek inhibitors. Here we report that Erk inhibitors result in efficient growth inhibition of tumor cells that are resistant to Raf and Mek inhibitors. AEZS-134 - a highly potent and selective ATP competitive Erk inhibitor - overcomes the Raf inhibitor induced paradoxical cell activation and the aquired resistance to Mek inhibitors in tumor cells. We demonstrate potent antiproliferative activity of AEZS-134 in B-Raf wildtype, B-RafV600E mutant, Ras wildtype and K-Ras mutant tumor cell lines in comparison to common Raf inhibitors. Furthermore we show that AEZS-134 is efficacious in Mek inhibitor resistant Hct116 and MDA MB231 cells which have been well characterized in terms of Mek F129L allosteric binding pocket mutation, varying degrees of K-Ras amplification, cellular proliferation assays and MAPK pathway phosphorylation studies. Our data provide a rational for new therapeutic opportunities by using Erk inhibitors in oncology. In order to maximize therapeutic benefit for patients and considering that Erk is directly downstream of B-Raf and Mek, targeting Erk may be more effective than targeting Raf or Mek in a variety of MAPK resistance settings. AEZS-134 and related compounds provide potent and selective tools to help address this question. Development of the Erk inhibitors by AEterna Zentaris is integral part of our inhouse kinase research program comprising the investigation of different compounds for single Erk inhibition, single PI3K inhibition and dual kinase inhibitions of Erk and PI3K. All compounds are exclusively synthesized by our medicinal chemistry department. Citation Format: Irene Seipelt, Peter Schmidt, Helene Maerzhaeuser, Matthias Gerlach, Kai Jung, Tilmann Schuster, Michael Teifel. Erk inhibition as a therapeutic option for the treatment of Raf- and Mek- inhibitor resistant tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3711. doi:10.1158/1538-7445.AM2014-3711