Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence
79 Pages Posted: 6 Apr 2018 Sneak Peek Status: PublishedMore...
Diverse pathways can drive resistance to BRAF and MEK inhibitors in BRAF mutant melanoma, suggesting that durable control of resistance will be a major challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of over 20 distinct 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 initial drug treatment, then rebounded during tumor progression independent of the upstream pathway driving resistance. Critically, MYC activation was both necessary and sufficient for resistance, and consequently, suppression of MYC activity using either genetic approaches or BET bromodomain inhibition was sufficient to both resensitize diverse BRAFi-resistant models and delay resistance in treatment naïve models. 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. Together, these insights enable the rational design of combination therapies that uniquely select against resistance evolution.
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