American Association for Cancer Research
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00085472can193782-sup-233330_3_supp_6391089_qcpnmd.pdf (25.75 MB)

Supplementary Data from Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non–Small Cell Lung Cancer

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posted on 2023-03-31, 03:27 authored by Fei Li, Wai-Lung Ng, Troy A. Luster, Hai Hu, Vladislav O. Sviderskiy, Catríona M. Dowling, Kate E.R. Hollinshead, Paula Zouitine, Hua Zhang, Qingyuan Huang, Michela Ranieri, Wei Wang, Zhaoyuan Fang, Ting Chen, Jiehui Deng, Kai Zhao, Hon-Cheong So, Alireza Khodadadi-Jamayran, Mousheng Xu, Angeliki Karatza, Val Pyon, Shuai Li, Yuanwang Pan, Kristen Labbe, Christina Almonte, John T. Poirier, George Miller, Richard Possemato, Jun Qi, Kwok-Kin Wong

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ARTICLE ABSTRACT

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 in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (Npm1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 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 NPM1 as a therapeutic vulnerability in NSCLC. Epigenome-wide CRISPR knockout screens identify NPM1 as a novel metabolic vulnerability and demonstrate that targeting NPM1 is a new therapeutic opportunity for patients with NSCLC.

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