PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

Abstract

Metastatic pancreatic neuroendocrine tumors (PNET) remain an unmet clinical problem. Chronologic 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 these tumors. It only delays disease progression in a subset of patients, while a significant fraction acquires resistance and shows 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 cross-talk 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 xenografts. These studies bring forward a well-grounded strategy for advanced PNETs that fail to respond to single-agent everolimus.

Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents

“…In vitro, KPT-9274 was found to synergize with Everolimus in cell growth inhibition, colony suppression, and glucose uptake. In vivo, the combination of KPT-9274 (150 mg/kg) with Everolimus (2.5 mg/kg) produced a statistically significant suppression in tumor growth, a scenario not observed for single agent of Everolimus (Mpilla et al, 2021). Mechanism study reveals that resistance to Everolimus is mainly due to activation of mTORC2, and treatment with the combination efficaciously resensitizes to BON-1 cell lines (Mpilla et al, 2021).…”

Review of various NAMPT inhibitors for the treatment of cancer

“…The only known drug that targets both NAMPT and PAK4 is KPT-9274, which is the subject of NCT02702492 listed in Table 1 . In this clinical trial, Gabriel et al concluded that KPT-9274 could make pancreatic neuroendocrine tumor cells more sensitive to traditional mTOR inhibitors, resulting in better therapeutic outcomes ( Mpilla et al, 2021 ). KPT-9274 has been demonstrated to modulate Wnt/β-linked protein signaling and decrease the growth of multiple tumor cell lines and subcutaneous xenograft models of mantle cell lymphoma.…”

Advances in Targeted Therapy for Patients with Neuroendocrine Tumours

“…PAK4 and NAMPT are mTOR regulators, which are aberrantly overexpressed in preclinical NET models and lead to everolimus resistance. 44 KPT-9274 is a PAK4-NAMPT dual inhibitor that, when administered at 150 mg/kg with everolimus (2.5 mg/kg), worked synergistically to suppress two pNET-derived xenografts. 44 Enhanced understanding of tumour biology and molecular behaviour of NETs may lead to the development of combinations to overcome tumour resistance mechanisms.…”