Abstract LB-B09: ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells

Abstract

Abstract Anti-cancer drugs commonly target signal transduction proteins activated by mutation. In patients with BRAFV600E melanoma, small molecule RAF and MEK kinase inhibitors cause dramatic but often transient tumor regression. Emerging evidence suggests that cancer cells adapting by non-genetic mechanisms constitute a reservoir for the development of drug-resistant tumors. Here, we show that few hours after exposure to RAF/MEK inhibitors, BRAFV600E melanomas undergo adaptive changes involving disruption of negative feedback and sporadic pulsatile reactivation of the MAPK pathway, so that MAPK activity is transiently high enough in some cells to drive proliferation. ERK pulses are locally triggered by autocrine/paracrine factors in the local microenvironment so that ERK activity levels are low on average, but transiently high enough in patches of cells to explain the infrequent division characteristic of persister cells. Quantitative proteomics and computational modeling show that pulsatile MAPK reactivation is possible due to the co-existence in cells of two MAPK cascades: one driven by BRAFV600E that is drug-sensitive and a second driven by receptors that is drug-resistant. Paradoxically, this may account both for the frequent emergence of drug resistance and for the tolerability of RAF/MEK therapy in patients. Citation Format: Luca Gerosa, Christopher Chidley, Fabian Froehlich, Gabriela Sanchez, Sang Kyun Lim, Jeremy Muhlich, Jia-Yun Chen, Gregory J. Baker, Denis Schapiro, Tujin Shi, Lian Yi, Carrie D. Nicora, Wei-Jun Qian, H. Steven Wiley, Peter Sorger. ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B09. doi:10.1158/1535-7163.TARG-19-LB-B09