Data from Epigenetic CRISPR Screens Identify <i>Npm1</i> as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

Abstract

<div>Abstract<p>Despite advancements in treatment options, the overall cure and survival rates for non–small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens <i>in vitro</i> and <i>in vivo</i> and identified the histone chaperone nucleophosmin 1 (<i>Npm1</i>) as a potential therapeutic target. Genetic ablation of <i>Npm1</i> significantly attenuated tumor progression <i>in vitro</i> and <i>in vivo</i>. Furthermore, <i>KRAS</i>-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of <i>Npm1</i> rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support <i>NPM1</i> as a therapeutic vulnerability in NSCLC.</p>Significance:<p>Epigenome-wide CRISPR knockout screens identify <i>NPM1</i> as a novel metabolic vulnerability and demonstrate that targeting <i>NPM1</i> is a new therapeutic opportunity for patients with NSCLC.</p></div>