| Summary: | Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, tumor remission varies unpredictably among patients and relapse is almost inevitable. Surprisingly, most of our current knowledge of tumor recurrence is derived from post-resistant tumor analyses, or single time-point drug response measurements. Very little is known about critical events during early response that precede resistance, or about the actual dynamics of drug response in treated melanoma cells. Filling this knowledge gap may engender key advances in targeted therapy of melanoma. To this end, we used an integrative approach using experimentation and mathematical modeling to quantify drug response dynamics in BRAF-mutated melanoma cells. Across all cell lines tested, we observed complex short-term responses (<100 h) varying from cell line to cell line. In contrast, the long-term dynamics were homogeneous, as all cell lines transitioned into a non-quiescent state of balanced death and division, which we term idling state. By applying a mathematical modeling framework of epigenetic landscape and phenotypic state transitions, we show that the observed population-level dynamics, in each cell line, can be interpreted as the result of a re-equilibration of the cell population across basins of attraction within drug-modified phenotypic landscapes. This modeling framework provides a unifying view of BRAF inhibition response dynamics in BRAF-mutated melanomas, whereby the short-term response is reflective of an initial re-equilibration process among distinct response phenotypic states, while idling constitutes the final equilibrated state. We propose that inferring the molecular drivers of the epigenetic landscapes that idling cells occupy before and after equilibration will provide rational therapeutic approaches to prevent or delay tumor recurrence.
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