Autophagy as a Mechanism for Adaptive Prediction-Mediated Emergence of Drug Resistance.

Drug resistance is a major problem in treatment of microbial infections and cancers. There is growing evidence that a transient drug tolerant state may precede and potentiate the emergence of drug resistance. Therefore, understanding the mechanisms leading to tolerance is critical for combating drug resistance and for the development of effective therapeutic strategy. Through laboratory evolution of yeast, we recently demonstrated that adaptive prediction (AP), a strategy employed by organisms to anticipate and prepare for a future stressful environment, can emerge within 100 generations by linking the response triggered by a neutral cue (caffeine) to a mechanism of protection against a lethal agent (5-fluoroorotic acid, 5-FOA). Here, we demonstrate that mutations selected across multiple laboratory-evolved lines had linked the neutral cue response to core genes of autophagy. Across these evolved lines, conditional activation of autophagy through AP conferred tolerance, and potentiated subsequent selection of mutations in genes specific to overcoming the toxicity of 5-FOA. These results offer a new perspective on how extensive genome-wide genetic interactions of autophagy could have facilitated the emergence of AP over short evolutionary timescales to potentiate selection of 5-FOA resistance-conferring mutations.