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Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer.
Cancer Res. 2020 Jul 09 [Online ahead of print]CR

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.

Authors+Show Affiliations

Perlmutter Cancer Center, New York University Langone Medical Center.School of Pharmacy, Chinese University of Hong Kong.Platform Biology, Intellia Therapeutics.Perlmutter Cancer Center, New York University Langone Medical Center.Department of Pathology, New York University School of Medicine.Perlmutter Cancer Center, New York University Langone Medical Center.Division of Radiation Oncology, New York University Langone Medical Center.Department of Cancer Biology, Dana-Farber Cancer Institute.Perlmutter Cancer Center, New York University Langone Medical Center.Shanghai Chest Hospital, Shanghai Jiao Tong University.Perlmutter Cancer Center, New York University Langone Medical Center.S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine.State Key Laboratory of Cell Biology, CAS center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences.Perlmutter Cancer Center, New York University Langone Medical Center.Perlmutter Cancer Center, New York University Langone Medical Center.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong.School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong.Applied Bioinformatics Laboratories, NYU Cancer Institute.Cancer Biology, DFCI.Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center.Perlmutter Cancer Center, New York University Langone Medical Center.cancer center, New York University School of Medicine.Perlmutter Cancer Center, New York University Langone Medical Center.Perlmutter Cancer Center, New York University Langone Medical Center.Department of Medical Oncology, Dana-Farber Cancer Institute.Perlmutter Cancer Center, New York University Langone Health.Department of Surgery and Cell Biology, New York University School of Medicine.Pathology, New York University School of Medicine.Cancer Biology, Dana-Farber Cancer Institute.Perlmutter Cancer Center, New York University Langone Medical Center kwok-kin.wong@nyumc.org.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32646968

Citation

Li, Fei, et al. "Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non-small Cell Lung Cancer." Cancer Research, 2020.
Li F, Ng WL, Luster TA, et al. Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer. Cancer Res. 2020.
Li, F., Ng, W. L., Luster, T. A., Hu, H., Sviderskiy, V. O., Dowling, C. M., Hollinshead, K. E. R., Zouitine, P., Zhang, H., Huang, Q., Ranieri, M., Wang, W., Fang, Z., Chen, T., Deng, J., Zhao, K., So, H. C., Khodadadi-Jamayran, A., Xu, M., ... Wong, K. K. (2020). Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-19-3782
Li F, et al. Epigenetic CRISPR Screens Identify Npm1 as a Therapeutic Vulnerability in Non-small Cell Lung Cancer. Cancer Res. 2020 Jul 9; PubMed PMID: 32646968.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer. AU - Li,Fei, AU - Ng,Wai-Lung, AU - Luster,Troy A, AU - Hu,Hai, AU - Sviderskiy,Vladislav O, AU - Dowling,Catríona M, AU - Hollinshead,Kate E R, AU - Zouitine,Paula, AU - Zhang,Hua, AU - Huang,Qingyuan, AU - Ranieri,Michela, AU - Wang,Wei, AU - Fang,Zhaoyuan, AU - Chen,Ting, AU - Deng,Jiehui, AU - Zhao,Kai, AU - So,Hon-Cheong, AU - Khodadadi-Jamayran,Alireza, AU - Xu,Mousheng, AU - Karatza,Angeliki, AU - Pyon,Val, AU - Li,Shuai, AU - Pan,Yuanwang, AU - Labbe,Kristen, AU - Almonte,Christina, AU - Poirier,John T, AU - Miller,George, AU - Possemato,Richard, AU - Qi,Jun, AU - Wong,Kwok-Kin, Y1 - 2020/07/09/ PY - 2020/07/06/accepted PY - 2019/12/02/received PY - 2020/04/03/revised PY - 2020/7/11/entrez JF - Cancer research JO - Cancer Res. N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/32646968/Epigenetic_CRISPR_screens_identify_Npm1_as_a_therapeutic_vulnerability_in_non-small_cell_lung_cancer L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=32646968 DB - PRIME DP - Unbound Medicine ER -
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