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| Status |
Public on Mar 14, 2024 |
| Title |
Dual-inhibition of NAMPT and PAK4 induces anti-tumor effects in platinum-resistant ovarian cancer by suppressing mitochondrial function and expression of genes related to inflammation and DNA repair. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Ovarian cancer follows a characteristic progression pattern, forming multiple tumor masses enriched with cancer stem cells (CSCs) within the abdomen. Most patients become resistant to standard platinum-based drugs, necessitating a change in treatment approach. To target CSCs, inhibiting NAMPT, which is the rate-limiting enzyme in the salvage pathway for NAD+ synthesis, has been explored. KPT-9274 is an innovative drug targeting both NAMPT and PAK4. However, its effectiveness against ovarian cancer had 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 expression of inflammation and gene repair-related genes. Moreover, by altering PAK4's mostly cytoplasmic localization, the compound hindered kinase activity, leading to decreased phosphorylation of S6 Ribosomal protein, AKT, and β-Catenin in the cytoplasm and its suppression was NAD+- dependent. These findings suggest that KPT-9274 could be a promising treatment for ovarian cancer patients resistant to platinum drugs, emphasizing the need for precision medicine to identify the specific NAD+-producing pathway a tumor relies on before treatment.
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| Overall design |
Total RNA obtained from ovarian cancer cell line with KPT-9274 treatment (24 hours) compared to untreated control cells.
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| Contributor(s) |
Kudo K, Greer YE, Yoshida T, Harrington BS, Korrapati S, Shibuya Y, Henegar L, Kopp JB, Fujii T, Lipkowitz S, Annunziata CM |
| Citation missing |
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| Submission date |
Dec 22, 2023 |
| Last update date |
Mar 14, 2024 |
| Contact name |
Kei Kudo |
| E-mail(s) |
kei.kudo@nih.gov
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| Phone |
3014763986
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| Organization name |
NIH
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| Street address |
9000 Rockville Pike
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA1055882 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE251890_RSEM_count.tar.gz |
55.8 Mb |
(ftp)(http) |
TAR |
SRA Run Selector |
| Raw data are available in SRA |
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