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Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non-Small Cell Lung Cancer
Fei Li1, Wai-Lung Ng2,3, Troy A Luster4
1Laura and Isaac Perlmutter Cancer Center, New York University Grossman School of Medicine, NYU Langone Health, New York, New York.
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. SIGNIFICANCE: 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.
Insights
Researchers identified nucleophosmin 1 (NPM1) as a key vulnerability in non-small cell lung cancer (NSCLC). Targeting NPM1 offers a new therapeutic strategy for NSCLC patients by altering cancer cell metabolism.
Area of Science:
- Oncology
- Epigenetics
- Cancer Metabolism
Background:
- Non-small cell lung cancer (NSCLC) has low cure and survival rates despite treatment advancements.
- Small-molecule inhibitors targeting epigenetic regulators show promise but have limited NSCLC application.
Purpose of the Study:
- To identify novel therapeutic targets in NSCLC by investigating epigenetic regulators.
- To explore the role of nucleophosmin 1 (NPM1) as a potential therapeutic target in NSCLC.
Main Methods:
- Performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo.
- Investigated the effect of NPM1 genetic ablation on NSCLC progression and metabolism.
- Analyzed the dependency of KRAS-mutant cancer cells on NPM1 expression.
Main Results:
- Identified NPM1 as a potential therapeutic target in NSCLC.
- Genetic ablation of NPM1 significantly inhibited tumor progression in vitro and in vivo.
- KRAS-mutant NSCLC cells demonstrated a higher addiction to NPM1.
- NPM1 ablation shifted cancer cell metabolism from aerobic glycolysis to oxidative phosphorylation.
- Reduced tumor-propagating cell populations were observed upon NPM1 ablation.
Conclusions:
- NPM1 represents a significant therapeutic vulnerability in NSCLC.
- Targeting NPM1 presents a novel therapeutic opportunity for NSCLC patients.
- NPM1 is a critical regulator of metabolic balance in NSCLC cells.
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