Alternative Treatment Strategies To Overcome Mapk Inhibitor Resistance In Melanoma

Inhibitors of the BRAF/MEK/ERK pathway have promise in the treatment of BRAF mutant melanoma and other MAPK activated cancers. Treatment of metastatic melanoma patients with the combination of RAF + MEK inhibitor has extended progression free survival over single agent therapy. However, in a large subset of patients, resistance invariably develops. Most clinical models show reactivation of the MAPK pathway in resistant samples, suggesting further downregulation of MAPK signaling might be beneficial. Therefore, we took BRAF mutant melanoma grown to resistance by continuous culture in dabrafenib plus trametinib (RAF + MEK inhibitor) or SCH772984 (ERK inhibitor), and treated them with a triple combination of RAF+MEK+ERK inhibitors. We found cells resistant to RAF+MEK inhibitors were cross-resistant to ERK inhibitor, but sensitive to RAF+MEK+ERK inhibitors. Conversely, cells resistant to the ERK inhibitor were cross-resistant to RAF+MEK inhibitor, but sensitive to the triple combination. However, given the possible deleterious side effects of a triple combination in patients, we explored whether alternative dosing and timing strategies could delay development of resistance. We compared chronic dosing of RAF+MEK or ERK inhibitors to weekly exposures alternating between RAF+MEK and ERK inhibitors. This alternative dosing strategy delayed development of resistance in vitro over chronic dosing, while also resulting in a slower proliferation rate in resistant cells. In addition, cells exposed to a higher dose of inhibitor for a shorter period of time was equivalent to chronic exposure. These studies suggest that alternative dosing strategies (other than chronic exposure) may prevent development of resistance, and allow for treatment of patients with higher order combinations and less side effects. Citation Format: Eva Goetz, Bokang Rabasha, Levi Garraway. Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2150.