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

Abstract

SUMMARY 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 over 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, 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.

Metabolic imaging using hyperpolarized 13C‐pyruvate to assess sensitivity to the B‐Raf inhibitor vemurafenib in melanoma cells and xenografts

“…[16][17][18][19][20] Resistance to BRAFi seems to be accompanied by precise metabolic changes as well: higher reliance on oxidative phosphorylation, [21][22][23][24] glutamine dependency 21,25,26 and up-regulated serine metabolism. 26,27 Besides suggesting novel targetable metabolic vulnerabilities, the fast-increasing knowledge in tumour metabolism will hopefully help identifying candidate biomarkers of clinical utility. To date, the lack of validated markers exploiting the aforementioned metabolic alterations to discriminate responding and non-responding melanomas in patients still hinders the long-term effectiveness of current treatment options and represents a barrier to the advancement of personalized medicine.…”

MYC Dysregulates Mitotic Spindle Function Creating a Dependency on TPX2

“…Finally, the reversibility of the observed MYC-induced spindle abnormalities and CIN indicates that MYC overexpression not only initiates CIN but is also required for its maintenance. Moreover, increased MYC expression has been observed in early tumor metastasis 69 (Lawson, 2015) and drug resistant cancers 70 , situations associated with CIN and tumor evolution. Several small molecule inhibitors that can modulate MYC transcriptional activity are currently under preclinical development and evaluation [71][72][73] .…”

Evolved resistance to GAPDH inhibition results in loss of the Warburg Effect but retains a different state of glycolysis

“…Cells were allowed to progress to resistance as previously described (Singleton et al, 2017). To allow cells to acquire resistance to KA, BT-549 breast cancer cells were first seeded in triplicate in 15cm plates at 3x10 6 cells per plate in normal media.…”