Next Article in Journal
WISP-1 Promotes Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells via the miR-153-3p/Snail Axis
Previous Article in Journal
Parallel Structure Deep Neural Network Using CNN and RNN with an Attention Mechanism for Breast Cancer Histology Image Classification
Open AccessArticle

PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors

1
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA
2
University of Detroit Mercy, Detroit, MI 48201, USA
3
Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA
4
Karyopharm Therapeutics Inc., Newton, MA 02459, USA
5
Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
*
Author to whom correspondence should be addressed.
Current address: Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Current address: resTORbio, Inc., Boston, MA 02116, USA
§
Current address: Department of Pathology, Northwestern University, Chicago, IL 60611, USA.
Cancers 2019, 11(12), 1902; https://doi.org/10.3390/cancers11121902
Received: 12 August 2019 / Revised: 16 November 2019 / Accepted: 18 November 2019 / Published: 29 November 2019
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. View Full-Text
Keywords: PAK4; NAMPT; mTOR; pancreatic neuroendocrine tumors; KPT-9274 PAK4; NAMPT; mTOR; pancreatic neuroendocrine tumors; KPT-9274
Show Figures

Figure 1

MDPI and ACS Style

Mpilla, G.; Aboukameel, A.; Muqbil, I.; Kim, S.; Beydoun, R.; Philip, P.A.; Mohammad, R.M.; Kamgar, M.; Shidham, V.; Senapedis, W.; Baloglu, E.; Li, J.; Dyson, G.; Xue, Y.; El-Rayes, B.; Azmi, A.S. PAK4-NAMPT Dual Inhibition as a Novel Strategy for Therapy Resistant Pancreatic Neuroendocrine Tumors. Cancers 2019, 11, 1902.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop