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

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 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.

The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells

“…The effect of SMYD2 silencing on cell proliferation was evaluated in the OVTOKO and OVISE cell lines, which have been previously used as representative OCCC cell lines ( 22 , 23 ), using two specific siRNAs against SMYD2. OVTOKO and OVISE cells were transfected with siSMYD2#1, siSMYD2#2 or siNC SMYD2 expression was evaluated using western blot analysis ( Fig.…”

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

“…FG-4592 was found to have no interference on the initiation, progression, or metastasis of cancer ( Seeley et al., 2017 ). However, recent studies showed an antitumor action of FG-4592 in macrophage-abundant tumors ( Nishide et al., 2019 ), and in human ovarian clear cell carcinoma ES2 cells ( Price et al., 2019 ). In another study, FG-4592 could selectively protect the intestinal tract from radiation toxicity without affecting pancreatic cancer ( Fujimoto et al., 2019 ).…”

“…HIF inhibitors are currently undergoing the clinical evaluation as anticancer drugs. However, recent studies showed that FG-4592 could inhibit tumor growth of macrophage-abundant tumors ( Nishide et al., 2019 ), and reduced viability and proliferation of human ovarian clear cell carcinoma ES2 cells ( Price et al., 2019 ), suggesting an antitumor potential of FG-4592. In the present study, the role and potential mechanisms of FG-4592 in DOX-induced cardiotoxicity were investigated.…”

Clear cell carcinoma of the ovary: a clinical and molecular perspective

“…123 This is consistent with the demonstration that HDAC6 inhibition can synergize with anti-PD-L1 therapy in a mouse model, raising the possibility that this combination may represent a novel therapeutic strategy. 124 In early work, prolyl hydroxylase domain-containing protein 2 (PHD2), encoded by EGLN1, has been identified as a potential hypoxia-inducible factor 1α (HIF1A)-dependent therapeutic target in clear cell carcinoma; 125 and screening of ARID1A-deficient cells has suggested that gemcitabine may be an effective therapeutic option in ARID1A-deficient tumors. 126 Post-Treatment Surveillance Current NCCN guidelines do not recommend clear cell carcinomaspecific post-treatment surveillance; 87 patients are followed up in the same way as patients with other histological tumor types.…”