PMID- 30898838
OWN - NLM
STAT- MEDLINE
DCOM- 20200214
LR  - 20210720
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 79
IP  - 10
DP  - 2019 May 15
TI  - Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear 
      Cell Ovarian Cancers.
PG  - 2564-2579
LID - 10.1158/0008-5472.CAN-18-2674 [doi]
AB  - 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 EGLN1, which encodes prolyl hydroxylase 
      domain-containing protein 2 (PHD2), reduced the proliferation of a subset of 
      clear cell ovarian cancer cell lines in vitro. 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.
CI  - (c)2019 American Association for Cancer Research.
FAU - Price, Colles
AU  - Price C
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Gill, Stanley
AU  - Gill S
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts.
FAU - Ho, Zandra V
AU  - Ho ZV
AUID- ORCID: 0000-0003-4046-0266
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Davidson, Shawn M
AU  - Davidson SM
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Merkel, Erin
AU  - Merkel E
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - McFarland, James M
AU  - McFarland JM
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Leung, Lisa
AU  - Leung L
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Tang, Andrew
AU  - Tang A
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Kost-Alimova, Maria
AU  - Kost-Alimova M
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Tsherniak, Aviad
AU  - Tsherniak A
AUID- ORCID: 0000-0002-3797-1877
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
FAU - Jonas, Oliver
AU  - Jonas O
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
AD  - Koch Institute for Integrative Cancer Research, Massachusetts Institute of 
      Technology, Cambridge, Massachusetts.
FAU - Vazquez, Francisca
AU  - Vazquez F
AUID- ORCID: 0000-0002-2857-4685
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts.
FAU - Hahn, William C
AU  - Hahn WC
AD  - Broad Institute of Harvard and MIT, Cambridge, Massachusetts. 
      william_hahn@dfci.harvard.edu.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
LA  - eng
GR  - P41 EB015898/EB/NIBIB NIH HHS/United States
GR  - R01 CA223150/CA/NCI NIH HHS/United States
GR  - T32 CA009361/CA/NCI NIH HHS/United States
GR  - U01 CA176058/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190321
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - CRISPR-Cas Systems
MH  - Cell Line, Tumor
MH  - Female
MH  - *Genome-Wide Association Study
MH  - Humans
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/*genetics
MH  - Ovarian Neoplasms/*genetics/pathology
MH  - RNA Interference
PMC - PMC6522283
MID - NIHMS1525136
EDAT- 2019/03/23 06:00
MHDA- 2020/02/15 06:00
PMCR- 2020/05/15
CRDT- 2019/03/23 06:00
PHST- 2018/08/28 00:00 [received]
PHST- 2019/01/18 00:00 [revised]
PHST- 2019/03/14 00:00 [accepted]
PHST- 2019/03/23 06:00 [pubmed]
PHST- 2020/02/15 06:00 [medline]
PHST- 2019/03/23 06:00 [entrez]
PHST- 2020/05/15 00:00 [pmc-release]
AID - 0008-5472.CAN-18-2674 [pii]
AID - 10.1158/0008-5472.CAN-18-2674 [doi]
PST - ppublish
SO  - Cancer Res. 2019 May 15;79(10):2564-2579. doi: 10.1158/0008-5472.CAN-18-2674. 
      Epub 2019 Mar 21.