Abstract 4827: Co-administration of nicotinic acid (NA) enhances the therapeutic index of KPT-9274 in cancer cells

Abstract

Abstract We have previously described the PAK4 allosteric modulators (PAMs), KPT-7523 and KPT-9274, as potent anti-cancer small molecules. We recently found that PAMs also inhibit nicotinamide phosphoribosyl transferase (NAMPT) enzymatic activity, a protein that forms a complex with PAK4 to help regulate cytoskeletal structures, cell adhesion and migration. NAMPT and nicotinate phosphoribosyl transferase (NAPRT1) catalyze the rate limiting steps in the nicotinamide adenine dinucleotide (NAD) salvage pathways. While NAMPT is frequently overexpressed in certain cancer types, NAPRT1 is often downregulated. NAD levels can be depleted under conditions of high metabolic demand (i.e. cancer cells) when consumed by other enzymes including poly-ADP ribose polymerases (PARPs) and sirtuins (SIRTs). In addition, induction of cancer cell death by NAD depletion can be mitigated by nicotinic acid (NA) supplementation in a NAPRT1 dependent manner. The purpose of this study is to determine whether KPT-9274 co-dosed with NA can reduce potential toxicities associated with NAD depletion, while enhancing anti-neoplastic activity in cancers lacking NAPRT1. Methods: Cyclex NAMPT colorimetric assay was used to examine NAMPT enzymatic activity in vitro. NAD/NADH-Glo and Celltiter-Glo were used to measure NAD and ATP levels, respectively. Gene expression and gene promoter methylation was determined using quantitative PCR and sequencing technologies. Western blot analysis was used to examine protein expression and protein-protein interactions. Results: We have identified an orally bioavailable dual inhibitor of PAK4 and NAMPT, KPT-9274, which demonstrated potent anti-cancer activity in a variety of cell lines both in vitro and in vivo. Cell death induced by KPT-9274 treatment in NAPRT1+ cells (COLO 205, Z-138, THP-1, MV-4-11) can be mitigated by NA, while NAPRT1- cells (COLO 320HSR, JeKo-1, REC-1, U-2 OS, PC-3) remain sensitive to KPT-9274 + NA. A reduction of both PAK4 protein levels and cell viability is still observed in these different cell types co-dosed with KPT-9274 + NA. In preliminary toxicology studies of KPT-9274 co-administered with NA in dogs, we observed a reduction in potential toxicity (i.e. gastrointestinal and hematological effects). In vivo assessment of KPT-9274 +/- NA and NAPRT1 status is on-going. Conclusions: Here we report that the therapeutic index of KPT-9274, the first-in-class dual inhibitor of PAK4 and NAMPT, can be enhanced when co-dosed with NA in cancers lacking NAPRT1 protein expression in vitro. Furthermore, KPT-9274 can still reduce steady state PAK4 levels and cell viability regardless of NAPRT1 status. Based on these data, co-administration of NA with KPT-9274 may be beneficial for the treatment of a wide variety of cancers and will be tested in phase 1 clinical development. Citation Format: William Senapedis, Christian Argueta, Yosef Landesman, Margaret Lee, Sharon Shacham, Erkan Balolgu. Co-administration of nicotinic acid (NA) enhances the therapeutic index of KPT-9274 in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4827.