ArticleClinical cancer research : an official journal of the American Association for Cancer Research2019
ERK Regulates HIF1α-Mediated Platinum Resistance by Directly Targeting PHD2 in Ovarian Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 47 citations in OpenAlex.
- The role of cytokines in ovarian cancer drug resistance.International journal of cancer · 2026Review
- DUSP5 contributes to platinum resistance in ovarian cancer: single-cell discovery and functional validation.Frontiers in pharmacology · 2026Article
- AND-1 is a critical regulator of R-loop dynamics and a target to overcome endocrine resistance.Science advances · 2025Article
- GPX3 promotes cisplatin resistance in TNBC by manipulating ROS-TGFB1-ZEB2.Cell communication and signaling : CCS · 2025Article
- Single-nucleus CUT&RUN elucidates the function of intrinsic and genomics-driven epigenetic heterogeneity in head and neck cancer progression.Genome research · 2025Article
- Recent advances in therapeutic use of transforming growth factor-beta inhibitors in cancer and fibrosis.Frontiers in oncology · 2025Review
- O-GlcNAcylation of MITF regulates its activity and CDK4/6 inhibitor resistance in breast cancer.Nature communications · 2024Article
- HSPA12A maintains aerobic glycolytic homeostasis and Histone3 lactylation in cardiomyocytes to attenuate myocardial ischemia/reperfusion injury.JCI insight · 2024Article
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- USP51/PD-L1/ITGB1-deployed juxtacrine interaction plays a cell-intrinsic role in promoting chemoresistant phenotypes in non-small cell lung cancer.Cancer communications (London, England) · 2023Article
- Targeting a thrombopoietin-independent strategy in the discovery of a novel inducer of megakaryocytopoiesis, DMAG, for the treatment of thrombocytopenia.Haematologica · 2023Article
- Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer: Current status in clinical trials.Genes & diseases · 2023Review
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- The multifaceted role of EGLN family prolyl hydroxylases in cancer: going beyond HIF regulation.Oncogene · 2022Review
- A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α-mediated aerobic glycolysis.Molecular oncology · 2022Article
- Revisiting chemoresistance in ovarian cancer: Mechanism, biomarkers, and precision medicine.Genes & diseases · 2022Review
- Sporoderm-Broken Spores ofFrontiers in pharmacology · 2022Article
- Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer.Cell reports. Medicine · 2021Article
- Review
Corrections and comments
- Erratum issued
Authors and funding
18 authors at 3 institutions in 3 countries.
Funding
Abstract
purposeUp to 80% of patients with ovarian cancer develop platinum resistance over time to platinum-based chemotherapy. Increased HIF1α level is an important mechanism governing platinum resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer. EXPERIMENTAL
designWe first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFβ1 (SB431542) with platinum drugs by
resultsYC-1 and selumetinib resensitized PROC cells to cisplatin. Next, the prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK. Phosphorylation of PHD2 by ERK prevents its binding to HIF1α, thus inhibiting HIF1α hydroxylation and degradation-increasing HIF1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGFβ1, promoting platinum resistance by stabilizing HIF1α. Inhibition of TGFβ1 by SB431542, ERK by selumetinib, or HIF1α by YC-1 efficiently overcame platinum resistance both
conclusionsHIF1α stabilization is regulated by TGFβ1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFβ1, ERK, or HIF1α is potential strategy for treating patients with PROC.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.