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Cancer Res DOI:10.1158/0008-5472.CAN-18-2674

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers.

Publication TypeJournal Article
Year of Publication2019
AuthorsPrice, C, Gill, S, Ho, ZV, Davidson, SM, Merkel, E, McFarland, JM, Leung, L, Tang, A, Kost-Alimova, M, Tsherniak, A, Jonas, O, Vazquez, F, Hahn, WC
JournalCancer Res
Volume79
Issue10
Pages2564-2579
Date Published2019 05 15
ISSN1538-7445
KeywordsCell Line, Tumor, CRISPR-Cas Systems, Female, Genome-Wide Association Study, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Ovarian Neoplasms, RNA Interference
Abstract

We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of , which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines . EGLN1-dependent cells exhibited sensitivity to the pan-EGLN inhibitor FG-4592. The response to FG-4592 was reversed by deletion of HIF1A, demonstrating that EGLN1 dependency was related to negative regulation of HIF1A. We also found that ovarian clear cell tumors susceptible to both genetic and pharmacologic inhibition of EGLN1 required intact HIF1A. Collectively, these observations identify EGLN1 as a cancer target with therapeutic potential. SIGNIFICANCE: These findings reveal a differential dependency of clear cell ovarian cancers on EGLN1, thus identifying EGLN1 as a potential therapeutic target in clear cell ovarian cancer patients.

DOI10.1158/0008-5472.CAN-18-2674
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30898838?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID30898838
PubMed Central IDPMC6522283
Grant ListP41 EB015898 / EB / NIBIB NIH HHS / United States
T32 CA009361 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States