ArticleMolecular cancer therapeutics2016
Dual and Specific Inhibition of NAMPT and PAK4 By KPT-9274 Decreases Kidney Cancer Growth.
Article in Molecular cancer therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 141 citations in OpenAlex.
- Metabolic reprogramming-mediated therapeutic resistance in renal cell carcinoma: Mechanisms and targeted intervention strategies.iScience · 2026Review
- Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor.Acta crystallographica. Section D, Structural biology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Metabolic reprogramming of myeloid cells in cancer: from lactate-NAMPT axis to AI-guided therapeutics.Experimental & molecular medicine · 2026Review
- PAK4 in metabolic diseases: regulation by nutrient signals and therapeutic implications.Experimental & molecular medicine · 2026Review
- First-in-Human Phase I Study of KPT-9274, a First-in-Class Dual Inhibitor of PAK4 and NAMPT, in Patients with Advanced Solid Malignancies.Targeted oncology · 2026Article
- Article
- Novel therapeutic strategies for ccRCC through integration of systemic drug combinations and oncolytic adenovirus immunotherapy.Frontiers in immunology · 2026Article
- P21-activated kinase 4: a potent oncogene, molecular mechanisms and opportunities for targeted therapy.Cancer cell international · 2025Review
- NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies withBlood neoplasia · 2025Article
- Visfatin promotes multiple myeloma cell proliferation and inhibits apoptosis by inducing IL-6 production via NF-κB pathways.Discover oncology · 2025Article
- Role of the tumor microenvironment in cancer therapy: unveiling new targets to overcome drug resistance.Medical oncology (Northwood, London, England) · 2025Review
- Design, synthesis and pharmacological evaluation of 1,2,3,4-tetrahydrobenzofuro[2,3-Acta pharmaceutica Sinica. B · 2025Article
- Comprehensive multi-omics analysis identifies NUSAP1 as a potential prognostic and immunotherapeutic marker for lung adenocarcinoma.International journal of medical sciences · 2025Article
- Mechanisms of resistance to NAMPT inhibitors in cancer.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Inhibition of NAMPT by PAK4 Inhibitors.International journal of molecular sciences · 2024Article
- TBC1D10B promotes tumor progression in colon cancer via PAK4‑mediated promotion of the PI3K/AKT/mTOR pathway.Apoptosis : an international journal on programmed cell death · 2024Article
- PAK4-targeted PROTACs in clear cell renal cell carcinoma: a two-for-one targeted and immune therapy?EBioMedicine · 2024Article
- Distinct Capabilities in NAD Metabolism Mediate Resistance to NAMPT Inhibition in Glioblastoma.Cancers · 2024Article
- Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.Journal of medicinal chemistry · 2024Review
30 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and one of the relatively few whose incidence is increasing. Because of the near universal resistance which occurs with the use of current treatment regimens, reprogrammed metabolic pathways are being investigated as potential targets for novel therapies of this disease. Borrowing from studies on other malignancies, we have identified the PAK4 and NAD biosynthetic pathways as being essential for RCC growth. We now show, using the dual PAK4/NAMPT inhibitor KPT-9274, that interference with these signaling pathways results in reduction of G2-M transit as well as induction of apoptosis and decrease in cell invasion and migration in several human RCC cell lines. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. Furthermore, NAPRT1 downregulation, which we show occurs in all RCC cell lines tested, makes this tumor highly dependent on NAMPT for its NAD requirements, such that inhibition of NAMPT by KPT-9274 leads to decreased survival of these rapidly proliferating cells. When KPT-9274 was administered in vivo to a 786-O (VHL-mut) human RCC xenograft model, there was dose-dependent inhibition of tumor growth with no apparent toxicity; KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC. Mol Cancer Ther; 15(9); 2119-29. ©2016 AACR.
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