A Nonquiescent "Idling" Population State in Drug-Treated, BRAF-Mutated Melanoma.

ABSTRACT

Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the "idling" state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to "targeted landscaping" therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.