Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Menées sur des lignées cellulaires d'adénocarcinome canalaire du pancréas et à l'aide de xénogreffes sur des modèles murins, ces études mettent en évidence l'intérêt d'une approche thérapeutique consistant à inhiber à la fois l'enzyme ERK ou MEK et le processus d'autophagie des cellules cancéreuses
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
Nature Medicine , résumé, 2019