Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population.

Publication date: Jul 29, 2021

Cancer cells within tumors display a high degree of phenotypic variability. This variability is thought to allow some of the cells to survive and persist after seemingly effective drug treatments. Studies on vemurafenib, a signaling inhibitor that targets an oncogenic BRAF mutation common in melanoma, suggested that cell-to-cell variation in drug resistance, measured by long-term proliferation, originates from epigenetic differences in gene expression that pre-exist treatment. However, it is still unknown whether reactivation of signaling downstream to the inhibited BRAF, thought to be a key step for resistance, is heterogeneous across cells. While previous studies established that signaling reactivation takes place many hours to days after treatment, they monitored reactivation with bulk-population assays unsuitable for detecting cell-to-cell heterogeneity. We hypothesized that signaling reactivation is heterogeneous and is almost instantaneous for a small subpopulation of resistant cells. We tested this hypothesis by monitoring signaling dynamics at a single-cell resolution and observed that despite highly uniform initial inhibition, roughly 15% of cells reactivated signaling within an hour of treatment. Moreover, by tracking cell lineages over multiple days, we established that these cells indeed proliferated more than neighboring cells, thus establishing that rapid signaling reactivation predicts long-term vemurafenib resistance.

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Concepts Keywords
Downstream Melanoma
Epigenetic BRAF
Hour Vemurafenib
Instantaneous Sulfonamides
Tumors Chloroarenes
Clinical medicine
MEK inhibitor


Type Source Name
disease MESH melanoma
pathway KEGG Melanoma
disease MESH Cancer
disease MESH phenotypic variability
drug DRUGBANK Vemurafenib
drug DRUGBANK Coenzyme M
drug DRUGBANK Oxygen
disease MESH growth
pathway REACTOME Signal Transduction
drug DRUGBANK Pentaerythritol tetranitrate
disease MESH separation
pathway KEGG Cell cycle
drug DRUGBANK Trestolone
disease MESH infection
drug DRUGBANK Esomeprazole
drug DRUGBANK Rifampicin
disease MESH recurrence
disease MESH lung adenocarcinoma
pathway KEGG Apoptosis
disease MESH carcinogenesis
disease MESH senescence
drug DRUGBANK Bismuth subgallate
drug DRUGBANK Rasagiline
disease MESH thyroid carcinoma

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