When do drug holidays delay resistance? A calibrated model of BRAF V600E melanoma

Treatment scheduling seeks to kill sensitive tumor cells while limiting resistance, but drug holidays can suppress drug-dependent resistant populations while allowing sensitive cells to regrow and subsequently replenish resistance through the persister state. We developed a calibrated mechanistic model of BRAF V600E melanoma to identify the biological conditions under which this trade-off favors intermittent treatment. The model links MAPK signaling and protein degradation to sensitive, persister, and resistant cell populations. Across 1,200 virtual tumors, scheduling benefit depended on resistant-cell growth relative to turnover and on loss of resistant-cell fitness after treatment withdrawal. Comparisons at equal cumulative exposure showed that timing itself altered resistance outcomes, although shorter cycles were not consistently better. Intermittent treatment delayed resistant disease more often than it improved overall progression, demonstrating that resistance delay alone is insufficient evidence of better tumor control. The study therefore provides a conditional map of scheduling benefit and a reusable framework for investigating the temporal responses of sensitive and resistant populations. Its population parameters remain experimentally underconstrained, and its representation of average cell behavior does not reproduce rare-cell persistence. With tumor-specific calibration and independent validation, this framework could guide the development of standardized models that balance sensitive-cell killing against resistance control.