ArticleCancers2019
PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors.
Article in Cancers, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the 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.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor.Acta crystallographica. Section D, Structural biology · 2026Article
- Article
- Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies.Medical oncology (Northwood, London, England) · 2025Review
- Molecular Characterization and Clinical Outcomes of Pancreatic Neuroendocrine Neoplasms Harboring PAK4-NAMPT Alterations.JCO oncology advances · 2025Article
- Combined blockade of mTOR and p21-activated kinases pathways prevents tumour growth in KRAS-mutated colorectal cancer.British journal of cancer · 2023Article
- Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity.Biomedicines · 2023Review
- Targeting NADFrontiers in immunology · 2023Review
- Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents.Frontiers in pharmacology · 2022Review
- Review of various NAMPT inhibitors for the treatment of cancer.Frontiers in pharmacology · 2022Review
- PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus.Molecular cancer therapeutics · 2021Article
- Regulation and metabolic functions of mTORC1 and mTORC2.Physiological reviews · 2021Review
- Progress in the therapeutic inhibition of Cdc42 signalling.Biochemical Society transactions · 2021Review
- Advances in NAD-Lowering Agents for Cancer Treatment.Nutrients · 2021Review
- NADSignal transduction and targeted therapy · 2021Review
- Physical activity differentially regulates VEGF, PlGF, and their receptors in the human placenta.Physiological reports · 2021Article
- Pancreatic neuroendocrine tumors: Therapeutic challenges and research limitations.World journal of gastroenterology · 2020Review
- Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy.Frontiers in oncology · 2019Review
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation.
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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.