The response of BRAF V600E/K melanoma patients to either RAF inhibitors or the RAF/MEK inhibitor combination is heterogeneous and short-term responses are associated with acquired resistance. Our previous studies have implicated compensatory FOXD3-ERBB3-AKT signaling as an adaptive response to targeted inhibition of the ERK1/2 pathway. While adaptive responses likely modulate the initial tumor response to targeted inhibitors, stable changes drive acquired resistance leading to the re-growth of tumors that initially responded to RAF inhibitors. Outgrowth of resistant cells may be due to the acquisition of a secondary mutation and/or selection of pre-existing cells harboring genetic alterations that negate the effect of RAF inhibitors. To model acquired resistance to RAF inhibitors, we developed mutant BRAF melanoma ERK1/2 activity reporter xenograft models. This system enables quantitative analysis of ERK1/2 activity in response to pathway inhibitors across the whole tumor in a temporal manner. We have utilized this system to analyze the initial response to RAF inhibitors in vivo, as well as re-activation of the ERK1/2 pathway associated with acquired resistance. Furthermore, we are utilizing this model to analyze response and resistance to RAF/MEK inhibitor combinations and next-generation RAF inhibitors.

Citation Format: Andrew E. Aplin. ERK activity in mutant BRAF melanoma – A live report. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA18.

©2015 American Association for Cancer Research.
2015