ArticleCancers2020
Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights.
Article in Cancers, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Trametinib Thwarts Activation of Survival Pathways Induced by Pro-ferroptotic Drug Conjugate ACXT-3102 Resulting in Enhanced Pancreatic Cancer Cell Death.Molecular cancer therapeutics · 2025Article
- The cGAS-STING pathway is a master regulator of OCT4 expression in persistent sarcoma cells and enhances cellular immunotherapy with NK and CIK lymphocytes.Cancer immunology, immunotherapy : CII · 2025Article
- Systemic strategies for osteosarcoma: advances and future directions.Discover oncology · 2025Review
- Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target.International journal of molecular sciences · 2025Review
- Cellular crosstalk in the bone marrow niche.Journal of translational medicine · 2024Review
- EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities.International journal of molecular sciences · 2024Review
- Targeting the EphA2 pathway: could it be the way for bone sarcomas?Cell communication and signaling : CCS · 2024Review
- The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies.International journal of molecular sciences · 2024Review
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- Combining Multikinase Tyrosine Kinase Inhibitors Targeting the Vascular Endothelial Growth Factor and Cluster of Differentiation 47 Signaling Pathways Is Predicted to Increase the Efficacy of Antiangiogenic Combination Therapies.ACS pharmacology & translational science · 2023Article
- Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario.Pharmaceutics · 2023Review
- Activity of pazopanib inOncoscience · 2023Article
- Mass Spectrometric-Based Proteomics for Biomarker Discovery in Osteosarcoma: Current Status and Future Direction.International journal of molecular sciences · 2022Review
- mTORC2 Is the Major Second Layer Kinase Negatively Regulating FOXO3 Activity.Molecules (Basel, Switzerland) · 2022Article
- Effect of Enterococcus faecalis OG1RF on human calvarial osteoblast apoptosis.BMC oral health · 2022Article
- The EPH/Ephrin System in Bone and Soft Tissue Sarcomas' Pathogenesis and Therapy: New Advancements and a Literature Review.International journal of molecular sciences · 2022Review
- Article
- Review
- Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment.Frontiers in cell and developmental biology · 2021Review
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 1 country.
Funding
Abstract
Receptor tyrosine kinases (RTKs) inhibitors' activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.
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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.