GSE117123
Intermittent Drug Treatment of BRAFV600E Melanoma Cells Delays Resistance by Sensitizing Cells to Rechallenge
Melanoma patients receiving drugs targeting BRAFV600E and MKK1/2 invariably develop resistance and continue progression, limiting the efficacy of treatment.  As an alternative to continuous dosing schedules, intermittent treatment strategies involving intervening periods of drug withdrawal have been proposed to delay resistance. The efficacy of this treatment strategy has been supported by preclinical findings and several clinical case reports. The beneficial effect of intermittent treatment has been attributed to “drug addiction”, in which the cell viability of resistant cells is compromised during periods of drug removal, presumably due to MAPK pathway hyperactivation. However, the cellular and molecular responses to intermittent treatment are still incompletely understood. Here, we investigate effects of intermittent treatment with the BRAFV600E inhibitor, encorafenib, in a metastatic melanoma cell line engineered to express genes conferring resistance to BRAF inhibition. We show that intermittent treatment shows superior growth suppression compared to continuous treatment for resistant cells that substantially reactivate the MAPK pathway.  While drug addiction is clearly observable in these cells, it fails to account for the advantageous effects of intermittent treatment. Instead, growth suppression can mainly be explained by resensitization as most cell death is observed upon readdition of drug following periods of drug removal. Gene expression analysis shows that a unique and reversible transcriptional state is induced in intermittently treated cells following periods of drug removal. Thus, we conclude that the beneficial effects of intermittent treatment in our model are best explained by adaptive, non-mutational changes in transcription which confer drug resensitization. Overall design: RNA-seq data from WM239A cells overexpressing BRAF V600E