Data from Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant <i>KRAS</i> Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function

Abstract

<div>Abstract<p>Ceramide kinase (CERK) is the mammalian lipid kinase from which the bioactive sphingolipid, ceramide-1-phosphate (C1P), is derived. CERK has been implicated in several promalignant phenotypes with little known as to mechanistic underpinnings. In this study, the mechanism of how CERK inhibition decreases cell survival in mutant (Mut) <i>KRAS</i> non–small cell lung cancer (NSCLC), a major lung cancer subtype, was revealed. Specifically, NSCLC cells possessing a <i>KRAS</i> mutation were more responsive to inhibition, downregulation, and genetic ablation of CERK compared with those with wild-type (WT) <i>KRAS</i> regarding a reduction in cell survival. Inhibition of CERK induced ferroptosis in Mut <i>KRAS</i> NSCLC cells, which required elevating VDAC-regulated mitochondria membrane potential (MMP) and the generation of cellular reactive oxygen species (ROS). Importantly, through modulation of VDAC, CERK inhibition synergized with the first-line NSCLC treatment, cisplatin, in reducing cell survival and <i>in vivo</i> tumor growth. Further mechanistic studies indicated that CERK inhibition affected MMP and cell survival by limiting AKT activation and translocation to mitochondria, and thus, blocking VDAC phosphorylation and tubulin recruitment.</p>Implications:<p>Our findings depict how CERK inhibition may serve as a new key point in combination therapeutic strategy for NSCLC, specifically precision therapeutics targeting NSCLC possessing a <i>KRAS</i> mutation.</p></div>