ArticleJournal of cellular physiology2019
Neratinib augments the lethality of [regorafenib + sildenafil].
Article in Journal of cellular physiology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02466802 (Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors), which is not on this map. Cited by 18 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.
Phase I Study of Regorafenib and Sildenafil for Advanced Solid Tumors
Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health.Frontiers in endocrinology · 2024Review
- Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling.Pigment cell & melanoma research · 2022Article
- Article
- The Potential Role of Sildenafil in Cancer Management through EPR Augmentation.Journal of personalized medicine · 2021Review
- New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil.Frontiers in oncology · 2021Review
- Axitinib and HDAC Inhibitors Interact to Kill Sarcoma Cells.Frontiers in oncology · 2021Article
- Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K, ERK1/2, and YAP/TAZ signaling.Journal of cellular physiology · 2020Article
- Fingolimod Augments Monomethylfumarate Killing of GBM Cells.Frontiers in oncology · 2020Article
- Not the comfy chair! Cancer drugs that act against multiple active sites.Expert opinion on therapeutic targets · 2019Review
- Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond.Nature reviews. Drug discovery · 2019Review
- Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers.Experimental & molecular medicine · 2019Review
- Lung cavitation in lung metastases of gastric and non-small-cell lung cancer patients treated with apatinib.Translational lung cancer research · 2019Article
- Prevalence and role of HER2 mutations in cancer.Pharmacology & therapeutics · 2019Review
- Review
- The Lethality of [Pazopanib + HDAC Inhibitors] Is Enhanced by Neratinib.Frontiers in oncology · 2019Article
- Kinase inhibitors: look beyond the label on the bottle.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- Neratinib and entinostat combine to rapidly reduce the expression of K-RAS, N-RAS, GαCancer biology & therapy · 2019Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib + sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia-telangiectasia-mutated (ATM)-AMP-dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death-ligand 1, ornithine decarboxylase, and indoleamine 2,3-dioxygenase-1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.
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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.