ArticleThe Journal of clinical investigation2021
Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer.Nature communications · 2026Article
- Role of the ETV5/p38 Signaling Axis in Aggressive Thyroid Cancer Cells.Molecular cancer therapeutics · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Targeting a super-enhancer induced aldehyde dehydrogenase metabolic loop mitigates CDK4/6 inhibitor resistance in estrogen receptor-positive cancers.Nature communications · 2026Article
- Rearrangement of 5-Indolyl-3-pyrrolin-2-ones into Privileged 4-Indolyl-3-pyrrolin-2-ones Leads to Identification of Antiproliferative Compounds Active under Hypoxia.The Journal of organic chemistry · 2026Article
- HDAC inhibitors in cancer therapy: sensitization mechanisms, combination strategies, and translational challenges.Frontiers in cell and developmental biology · 2026Review
- Establishment and characterization of a new immortalized human oral keratinocyte (HOK) cell line harboring various TP53 mutations.Oral oncology · 2026Article
- Pathway-Specific Therapeutic Modulation of Melanoma: Small-Molecule Inhibition of BRAF-MEK and KIT Signaling in Contemporary Precision Oncology with a Special Focus on Vemurafenib, Trametinib, and Imatinib.Journal of clinical medicine · 2025Review
- G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer cells.Genome biology · 2025Article
- Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.Cell death discovery · 2025Review
- Comprehensive bioinformatics analysis of omics data to reveal molecular mechanisms and biomarkers in multiple cancers.In silico pharmacology · 2025Article
- Epigenetic regulation espeically histone modifications in breast cancer: A viable and emerging targeted therapeutic strategy.Journal of Cancer · 2025Review
- CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.Science translational medicine · 2024Article
- 4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.JCI insight · 2024Article
- Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation.Molecular cancer · 2024Article
- Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises.Cancers · 2022Review
- RAD21 amplification epigenetically suppresses interferon signaling to promote immune evasion in ovarian cancer.The Journal of clinical investigation · 2022Article
- Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.Frontiers in oncology · 2022Article
- Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
28 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.
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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.