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

• Authors: Gabriel Mpilla, Wayne State University; Amro Aboukameel, Wayne State University; Irfana Muqbil, University of Detroit Mercy; Steve Kim, Wayne State University; Rafic Beydoun, Wayne State University; Philip A Philip, Wayne State University; Ramzi M Mohammad, Wayne State University; Mandana Kamgar, Wayne State University; Vinod Shidham, Wayne State University; Bassel El-Rayes, Emory University
• Journal Title: Cancers
• Volume: Volume 11, Number 12
• Publisher: MDPI | 2019-12-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3390/cancers11121902
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; PAK4; NAMPT; mTOR; pancreatic neuroendocrine tumors; KPT-9274; TARGET; CELLS; EXPRESSION; EVEROLIMUS; AGENTS; GENES

Abstract

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.