Fig. 8: Model describing how rapid, non-genetic drug adaptation can lead to bona fide drug resistance.

Dabrafenib-treated melanoma cells initially use non-genetic mechanisms, such as ATF4 stress signalling, to adapt to and escape from drug-induced quiescence. These early drug-adapted escapees incur DNA damage while cycling in drug, yet out-proliferate non-escapees over extended drug treatment. Thus, escapees are more likely than non-escapees to acquire the genetic mutations that lead to permanent drug resistance.