PAK4-NAMPT Dual Inhibition Sensitizes Pancreatic Neuroendocrine Tumors to Everolimus

• Type of Material: Article
• Authors: Gabriel B Mpilla, Wayne State University; Md Hafiz Uddin, Wayne State University; Mohammed N Al-Hallak, Wayne State University; Amro Aboukameel, Wayne State University; Yiwei Li, Wayne State University; Steve H Kim, Wayne State University; Rafic Beydoun, Wayne State University; Gregory Dyson, Wayne State University; Erkan Baloglu, Karyopharm Therapeutics; William T Senapedis, Karyopharm Therapeutics; Yosef Landesman, Karyopharm Therapeutics; Kay-Uwe Wagner, Wayne State University; Nerissa T Viola, Wayne State University; Bassel El-Rayes, Emory University; Philip A Philip, Wayne State University; Ramzi M Mohammad, Wayne State University; Asfar S Azmi, Wayne State University
• Language: English
• Date: 2021-10-01
• Publisher: AACR Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-20-1105
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• Volume: 20
• Issue: 10
• Start Page: 1836
• End Page: 1845
• Grant/Funding Information: Work in the lab of Azmi AS is supported by R01CA24060701 and SKY Foundation Inc.
• Keywords: Xenograft Model Antitumor Assays; Cell Proliferation; Apoptosis; Tumor Cells, Cultured; Animals; Drug Therapy, Combination; Everolimus; Humans; p21-Activated Kinases; Mice; Nicotinamide Phosphoribosyltransferase; Antineoplastic Agents; Female; Cytokines; Aminopyridines; Mice, Inbred ICR; Mice, SCID; Gene Expression Regulation, Neoplastic; Acrylamides; Pancreatic Neoplasms; Neuroendocrine Tumors

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 b-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.