GSE99923
Melanoma therapeutic strategies that select against resistance by exploiting MYC-driven evolutionary convergence
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, 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. Suppression of MYC activity using either genetic approaches or BET bromodomain inhibition was sufficient to both sensitize diverse BRAFi/MEKi-resistant models and delay resistance in treatment naïve models. Although direct pharmacological inhibition of MYC remains difficult, the BRAFi/MEKi-resistant, MYC-activated state harbors “synthetic lethal” signaling and metabolic dependencies, including those involving SRC family and c-KIT tyrosine kinases as well as glucose, glutamine, and serine metabolic pathways, that can be targeted to create combination therapies that uniquely select against resistance evolution. Overall design: Total RNA was isolated from A375 cells in biological triplicates in the following conditions: A375, A375-PLX4720 resistant clonal population, A375-MYC T58A, A375-PLX4720 resistant+shMYC