Evolutionary triage governs fitness in driver and passenger mutations and suggests targeting never mutations

摘要: Genetic and epigenetic changes in cancer cells are typically divided into 'drivers' 'passengers'. Drug development strategies target driver mutations, but inter- intratumoral heterogeneity usually results emergence of resistance. Here we model evolution the context a fecundity/survivorship trade-off. Simulations demonstrate that fitness value any genetic change is not fixed dependent on evolutionary triage governed by initial cell properties, current selection forces prior genotypic/phenotypic trajectories. We spatial variations molecular properties tumour result environmental such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations decrease burden almost inevitably fail due to population heterogeneity. An alternative strategy targets gene never observed. Because up or downregulation these genes unconditionally reduces cellular fitness, they eliminated can be exploited for targeted therapy.