PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Metastatic pancreatic neuroendocrine tumors (PNETs) remain an unmet clinical problem. Chronological treatment in PNETs includes observation (watchful protocol), surgery, targeted therapy, and chemotherapy. However, increasing evidence illustrates that the outcomes of targeted therapeutic options for the treatment of advanced PNETs show minimal response. The FDA approved mTOR inhibitor everolimus does not shrink patient's tumors. It only delays disease progression that too in only a subset of patients while a significant fraction acquire resistance and show disease progression. Thus, there is a need for more effective targeted approaches to sensitize PNETs to everolimus for better treatment outcomes. Previously, we showed that mTOR regulator p21 activated kinase 4 (PAK4) and nicotinamide adenine dinucleotide biosynthesis enzyme nicotinamide phosphoribosyl transferase (NAMPT) were aberrantly expressed in PNET tissue and promoted everolimus resistance. In this report, we demonstrate that PAK4-NAMPT dual inhibitor KPT-9274 can synergize with everolimus (growth inhibition, colony suppression and glucose uptake assays). KPT-9274-everolimus disrupted spheroid formation in multiple PNET models. Molecular analysis showed alteration of mTORC2 through downregulation of RICTOR as a mechanism supporting synergy with everolimus in vitro. KPT-9274 suppressed β-catenin activity via inhibition of PAK4 highlighting the crosstalk between Rho GTPases and Wnt signaling in PNETs. KPT-9274, given at (150 mg/kg) in combination with sub-MTD everolimus (2.5 mg/kg) significantly suppressed two PNET derived xenograft. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.