TY - JOUR T1 - Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAF<sup>V600E</sup> melanoma cells JF - bioRxiv DO - 10.1101/762294 SP - 762294 AU - Luca Gerosa AU - Christopher Chidley AU - Fabian Froehlich AU - Gabriela Sanchez AU - Sang Kyun Lim AU - Jeremy Muhlich AU - Jia-Yun Chen AU - Gregory J. Baker AU - Denis Schapiro AU - Tujin Shi AU - Lian Yi AU - Carrie D. Nicora AU - Allison Claas AU - Douglas A. Lauffenburger AU - Wei-Jun Qian AU - H. Steven Wiley AU - Peter K. Sorger Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/08/762294.abstract N2 - 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. 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. ER -