Figure 5: Schema depicting the effects of PIKfyve inhibition and KRAS-MAPK inhibition.

(Top left) With functional PIKfyve and KRAS-MAPK signaling, PDAC is at metabolic homeostasis, able to generate lipids both through de novo synthesis as well as through lysosomal processes. (Top right) Upon PIKfyve inhibition, autophagy and lysosomal functions are disrupted, forcing PDAC to upregulate and depend on de novo fatty acid synthesis through FASN and ACC1. (Bottom left) KRAS-MAPK inhibition decreases expression of FASN and ACC1 and increases PDAC cells’ dependence on autophagy and lysosomal processes. (Bottom right) concurrent PIKfyve and KRAS-MAPK inhibition results in lethal metabolic crises in PDAC.