Abstract 2343: A novel ERK inhibitor is active in models of acquired resistance to BRAF and MEK inhibitors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The high frequency of activating BRAFV600E mutations in melanoma (40-70%), thyroid (50%) and colorectal cancer (10%), or KRAS/NRAS mutations in melanoma (20%), pancreatic (90%), colorectal (50%) and non-small cell lung cancer (30%), provides strong rationale for targeting the MAPK pathway as a therapeutic strategy 1-6. Vemurafenib (PLX4032) and dabrafenib (GSK2118436), selective BRAF inhibitors, and trametinib (GSK1120212), an allosteric MEK inhibitor, have shown robust clinical efficacy in melanoma patients 7-10. However, the majority of responses are transient and cellular resistance is often associated with pathway reactivation involving the downstream extracellular-signal-regulated kinases 1 and 2 (ERK1/2) (reviewed in 11). We hypothesized that pathway blockade at ERK, the last signaling node prior to MAPK transcriptional programming, would not only be efficacious in MAPK-activated tumors but would also have utility in BRAF or MEK inhibitor resistant settings. We therefore sought to identify small molecule inhibitors of ERK. This report describes the identification and characterization of SCH772984, a potent and selective ATP competitive inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency on tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor resistant models as well as in the context of BRAF/MEK combination resistance. Together these data support the clinical development of ERK inhibitors, not only in patients with MAPK activated tumors, but also in patients who have developed acquired resistance to BRAF or MEK inhibitors or resistance to the recently described combination of these agents. Citation Format: Ahmed A. Samatar, Erick J. Morris, Sharda Jha, Restaino R. Clifford, Bart Luttrerbach, Marc Pelletier, Ulrike Philippar, Lata Jayaraman, Leigh Zawel, Steve Fawell, Gary Gilliland. A novel ERK inhibitor is active in models of acquired resistance to BRAF and MEK 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 2343. doi:10.1158/1538-7445.AM2013-2343