NADK is Activated by Oncogenic KRAS Signaling to Sustain Pancreatic Ductal Adenocarcinoma

Abstract

Metabolic adaptations and the signaling events that control them have been implicated in the adaptation of pancreatic ductal adenocarcinoma (PDAC) to survive stresses associated with nutrient and oxygen deprivation at the tumor site. Recently, rewiring of NADPH production has been shown to play a key role in this process. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is only synthesized through one known enzymatic reaction, catalyzed by NAD+ kinase (NADK). In this study, we show that oncogenic KRAS promotes PKC-mediated NADK phosphorylation and consequently leads to its hyperactivation, a phenomenon that is essential for sustaining NADPH levels and redox balance in PDAC cells. Together, our data show that increased NADK activity is an essential adaptation driven by oncogenic KRAS signaling. Our finding indicates that NADK could serve as a new and much-needed therapeutic target for PDAC.