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.