Abstract 3928: In vivo ERK1/2 reporting demonstrates the association and timing of ERK1/2 pathway reactivation and acquired resistance to RAF inhibitors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Patients with V600 mutant BRAF positive metastatic melanoma are now treated with the RAF inhibitor, vemurafenib (Zelboraf), as a first line therapy. Although most patients treated with vemurafenib have tumor shrinkage, other patients exhibit disease progression. Furthermore, most patients who initially respond to the drug eventually develop acquired resistance to vemurafenib. Disease progression while on vemurafenib frequently correlates with ERK1/2 pathway reactivation but previous studies have been unable to precisely monitor the temporal changes in ERK1/2 activity. Here, we establish a cell-based ERK1/2 reporter system that provides quantitative analysis of RAF inhibitor action in mutant BRAF melanoma cells in vitro and in vivo. This system was utilized to show that the RAF inhibitor, PLX4720, effectively targets the ERK1/2 pathway in vivo and that ERK1/2 reactivation is associated with tumor re-growth. Levels of ERK1/2 reactivation varied substantially between tumors and were associated with several different molecular changes. These data present a new system from monitoring in vivo efficacy of ERK1/2 pathway inhibitors and identifying mechanisms of in vivo acquired resistance. Citation Format: Kevin J. Basile, Ethan V. Abel, Neda Dadpey, Andrew E. Aplin. In vivo ERK1/2 reporting demonstrates the association and timing of ERK1/2 pathway reactivation and acquired resistance to RAF inhibitors. [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 3928. doi:10.1158/1538-7445.AM2013-3928