ArticleProceedings of the National Academy of Sciences of the United States of America2014
Bisphosphonates inactivate human EGFRs to exert antitumor actions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 60 citations in OpenAlex.
- Bisphosphonates and risk of cancers: a systematic review and meta-analysis.British journal of cancer · 2020Pooled it
- Oral bisphosphonates and colorectal cancer.Scientific reports · 2017Trial
- Biomaterial-based strategies for bone cement: modulating the bone microenvironment and promoting regeneration.Journal of nanobiotechnology · 2025Review
- RNA-Binding Proteins as Novel Effectors in Osteoblasts and Osteoclasts: A Systems Biology Approach to Dissect the Transcriptional Landscape.International journal of molecular sciences · 2024Article
- Engineering Bifunctional Calcium Alendronate Gene-Delivery Nanoneedle for Synergistic Chemo/Immuno-Therapy Against HER2 Positive Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
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- Article
- Review
- Carrier-free multifunctional nanomedicine for intraperitoneal disseminated ovarian cancer therapy.Journal of nanobiotechnology · 2022Article
- Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment.Genes · 2022Article
- Role of Phosphorus-Containing Molecules on the Formation of Nano-Sized Calcium Phosphate for Bone Therapy.Frontiers in bioengineering and biotechnology · 2022Article
- Current progress and future perspectives of polypharmacology : From the view of non-small cell lung cancer.Seminars in cancer biology · 2021Review
- Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques.Frontiers in endocrinology · 2021Review
- A Drug Holiday Reduces the Frequency and Severity of Medication-Related Osteonecrosis of the Jaw in a Minipig Model.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2020Article
- Beyond bone biology: Lessons from team science.Journal of orthopaedic research : official publication of the Orthopaedic Research Society · 2020Article
- miR-122 Exerts Inhibitory Effects on Osteoblast Proliferation/Differentiation in Osteoporosis by Activating the PCP4-Mediated JNK Pathway.Molecular therapy. Nucleic acids · 2020Article
- The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb.International journal of molecular sciences · 2019Article
- miR-101-3p/Rap1b signal pathway plays a key role in osteoclast differentiation after treatment with bisphosphonates.BMB reports · 2019Article
- A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.Science advances · 2019Article
- Current state and outlook for drug repositioning anticipated in the field of ovarian cancer.Journal of gynecologic oncology · 2019Review
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Authors and funding
27 authors at 5 institutions in 4 countries.
Funding
Abstract
Bisphosphonates are the most commonly prescribed medicines for osteoporosis and skeletal metastases. The drugs have also been shown to reduce cancer progression, but only in certain patient subgroups, suggesting that there is a molecular entity that mediates bisphosphonate action on tumor cells. Using connectivity mapping, we identified human epidermal growth factor receptors (human EGFR or HER) as a potential new molecular entity for bisphosphonate action. Protein thermal shift and cell-free kinase assays, together with computational modeling, demonstrated that N-containing bisphosphonates directly bind to the kinase domain of HER1/2 to cause a global reduction in downstream signaling. By doing so, the drugs kill lung, breast, and colon cancer cells that are driven by activating mutations or overexpression of HER1. Knocking down HER isoforms thus abrogates cell killing by bisphosphonates, establishing complete HER dependence and ruling out a significant role for other receptor tyrosine kinases or the enzyme farnesyl pyrophosphate synthase. Consistent with this finding, colon cancer cells expressing low levels of HER do not respond to bisphosphonates. The results suggest that bisphosphonates can potentially be repurposed for the prevention and therapy of HER family-driven cancers.
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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.