ArticleCancer gene therapy2024
Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in 3D-spheroids model of platinum-resistant ovarian cancer.
Article in Cancer gene therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 9 citations in OpenAlex.
- Structural basis for a p21-activated kinase 4 and nicotinamide phosphoribosyltransferase dual inhibitor.Acta crystallographica. Section D, Structural biology · 2026Article
- Nanomedicine-powered redox homeostasis modulation: Disrupting antioxidant systems and inducing oxidative stress for precision tumor therapy.Materials today. Bio · 2026Review
- Investigating PAK inhibition in combination with PD-1 blockade to enhance cytotoxic CD8+ T cell-mediated killing and suppress invasion of ovarian cancer cells.British journal of cancer · 2026Article
- 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
- P21-activated kinase 4: a potent oncogene, molecular mechanisms and opportunities for targeted therapy.Cancer cell international · 2025Review
- A Comprehensive Multiomics Signature of Doxorubicin-Induced Cellular Senescence in the Postmenopausal Human Ovary.Aging cell · 2025Article
- Targeting metabolic vulnerability by combining NAMPT inhibitors and disulfiram for treatment of recurrent ovarian cancer.Cell death & disease · 2025Article
- Tryptophan metabolism at the crossroads of the neuro-immuno-microbial axis: implications for precision medicine in chronic diseases.Frontiers in cellular and infection microbiology · 2025Review
- Comprehensive multi-omics analysis identifies NUSAP1 as a potential prognostic and immunotherapeutic marker for lung adenocarcinoma.International journal of medical sciences · 2025Article
- Biological Functions and Therapeutic Potential of NADCancers · 2024Review
- Article
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Ovarian cancer follows a characteristic progression pattern, forming multiple tumor masses enriched with cancer stem cells (CSCs) within the abdomen. Most patients develop resistance to standard platinum-based drugs, necessitating better treatment approaches. Targeting CSCs by inhibiting NAD+ synthesis has been previously explored. Nicotinamide phosphoribosyltransferase (NAMPT), which is the rate limiting enzyme in the salvage pathway for NAD+ synthesis is an attractive drug target in this pathway. KPT-9274 is an innovative drug targeting both NAMPT and p21 activated kinase 4 (PAK4). However, its effectiveness against ovarian cancer has not been validated. Here, we show the efficacy and mechanisms of KPT-9274 in treating 3D-cultured spheroids that are resistant to platinum-based drugs. In these spheroids, KPT-9274 not only inhibited NAD+ production in NAMPT-dependent cell lines, but also suppressed NADPH and ATP production, indicating reduced mitochondrial function. It also downregulated of inflammation and DNA repair-related genes. Moreover, the compound reduced PAK4 activity by altering its mostly cytoplasmic localization, leading to NAD+-dependent decreases in phosphorylation of S6 Ribosomal protein, AKT, and β-Catenin in the cytoplasm. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients who are resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+ producing pathway that a tumor relies upon before treatment.
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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.