Treatment of BRAF‐mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live‐cell imaging, single‐cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug‐adapted cells up‐regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug‐naïve state within 9 days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c‐Jun/ECM/FAK/Src cascade in de‐differentiation in about one‐third of cell lines studied; drug‐induced changes in c‐Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c‐Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (E max) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single‐cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations.

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[1] We surveyed 10 years of CANOPUS Churchill line magnetometer data for Pc5 pulsations and catalogued over 4500 hours of pulsation activity (3334 Pc5 pulsation intervals). Many previously observed Pc5 pulsation characteristics are evident in our data including the dawn/dusk occurrence asymmetry, antisunward propagation patterns, strong correlations between Pc5 band power spectral density (PSD) and solar wind flow speed, increased Pc5 pulsation occurrence during times of high solar wind speeds, and statistical evidence for Pc5 pulsation polarization sense reversals in latitude and local time (across local noon). Our investigation also revealed some as of yet unreported results such as a good correlation between solar wind speed/Pc5 band PSD in all MLT sectors, increased Pc5 pulsation occurrence with IMF B z northward conditions (for all MLTs), and the prevalence of Pc5 pulsations under all Pc5 band relative power values. We used a subset of 800 data intervals which contained Pc5 pulsations in at least three Churchill line stations to search for pulsations that exhibit classic FLR characteristics. Four hundred and fifty of these pulsations matched the FLR criteria and we discovered that the FLR MLT occurrence distribution is asymmetric about local noon with more pulsations occurring in the morning sector (0600-1200 MLT) than the afternoon sector (1200-1800 MLT), and an absence of FLRs at local noon. We also found that the MLT occurrence distribution for the remaining 350 ''non-FLR'' pulsations is symmetric about local noon and has a (nonzero) local minimum at noon. In contradiction with the results of some previous studies, we find no evidence of stable, recurring, discrete Pc5 pulsation frequencies in our data set. Instead, our statistics show a continuous distribution of central frequencies and a general lack of frequency stability throughout the course of individual Pc5 pulsation events.