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

Publication date: 5 December 2017
Source:Cell Reports, Volume 21, Issue 10
Author(s): Katherine R. Singleton, Lorin Crawford, Elizabeth Tsui, Haley E. Manchester, Ophelia Maertens, Xiaojing Liu, Maria V. Liberti, Anniefer N. Magpusao, Elizabeth M. Stein, Jennifer P. Tingley, Dennie T. Frederick, Genevieve M. Boland, Keith T. Flaherty, Shannon J. McCall, Clemens Krepler, Katrin Sproesser, Meenhard Herlyn, Drew J. Adams, Jason W. Locasale, Karen Cichowski, Sayan Mukherjee, Kris C. Wood
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.

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Teaser

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, but by combining statistical modeling of tumor data with functional interrogation of resistance models, Singleton et al. show that these pathways converge to activate MYC. BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, informing therapies that select against resistance.


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