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A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.

ABSTRACT: Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative. PAK4 is also overexpressed in other types of cancer, making it a promising drug target. However, its inhibition is complicated by the fact that PAK4 has both kinase-dependent and -independent functions. Here we investigate a new clinical compound KPT-9274, which has been shown to inhibit PAK4 and NAMPT. We find that KPT-9274 (and its analog, KPT-8752) can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. These compounds also block the growth of the breast cancer cells in vitro, and stimulate apoptosis. Most importantly, oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. Our results indicate that KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy.

SUBMITTER: Rane C

PROVIDER: S-EPMC5309789 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.

Rane Chetan C Senapedis William W Baloglu Erkan E Landesman Yosef Y Crochiere Marsha M Das-Gupta Soumyasri S Minden Audrey A

Scientific reports 20170215

Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which ar ...[more]

PMID: 28198380

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Project description:Abstract BACKGROUND Current treatment of glioblastoma (GBM) with surgery and chemoRT yields an average survival of ~1.5 years, highlighting the need for more effective therapies. We have previously reported that PAK4 is a key modulator of radioresistance in GBM. Additionally, pathways that regulate differential energy metabolism in gliomas and circumvent tumor heterogeneity have recently emerged as promising therapeutic targets. We hypothesized that inhibition of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, a key pathway preferentially used in glioma energy metabolism, would be effective against GBM. METHODS We tested the efficacy of KPT9274, a potent first-in-class dual inhibitor of PAK4 and NAMPT, currently in human trials against solid tumors and lymphomas (NCT02702492), on NAD levels and cell viability in glioma cell lines and patient-derived glioma stem-like cells (GSC). We also examined enzyme-kinetics of various components of the NAD salvage pathway and effects of NADH rescue by nicotinamide, NMN and NAD. Lastly, we examined the biological relevance of NAMPT inhibition in glioma cells and GSC using a combination of cell adhesion, wound-healing, transwell-migration and microtubule formation assays. RESULTS Treatment with KPT9274 resulted in potent depletion of NAD in glioma cells which was rescued by nicotinamide, NMN and NAD demonstrating its specificity against NAMPT. KPT-9274 treatment resulted in potent inhibition of cell adhesion, migration, cell invasion, endothelial tube formation and proliferation in glioma cells and GSC. In vivo studies in mouse bioluminescent intracranial glioma PDX model as well as PK studies are ongoing to confirm the pre-clinical significance of targeting NAMPT in gliomas and will be presented. CONCLUSIONS Our study demonstrates a key role for NAMPT in NAD generation in gliomas as seen by the potent biological effects of KPT-9274 against these tumors and supports the potential for targeting the NAD salvage pathway as a novel therapeutic strategy for treatment of GBM.

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A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.

Publications

A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.

Similar Datasets

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