Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence

作者：Singleton Katherine R; Crawford Lorin; Tsui Elizabeth; Manchester Haley E; Maertens Ophelia; Liu Xiaojing; Liberti Maria V; Magpusao Anniefer N; Stein Elizabeth M; Tingley Jennifer P; Frederick Dennie T; Boland Genevieve M; Flaherty Keith T; McCall Shannon J; Krepler Clemens; Sproesser Katrin; Herlyn Meenhard; Adams Drew J; Locasale Jason W; Cichowski Karen; Mukherjee Sayan; Wood Kris C^*

来源：Cell Reports, 2017, 21(10): 2796-2812.

DOI：10.1016/j.celrep.2017.11.022

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of > 20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

• 出版日期2017-12-5