Pancreatic Neuroendocrine Tumors (PNETs) remains an unmet clinical problem and epidemiologic studies indicate that their incidence has significantly increased over the years. Surgery remains the only curative option in patients with localized tumors. However, there is no effective therapy in patients with advanced or metastatic disease. Thus, unfortunately, 65% of PNET patients with advanced/unresectable disease die within 5 years after diagnosis. Current therapeutic approaches for advanced PNET patients include chemotherapy (Capecitabine, Temolozomide, 5FU etc), targeted therapies (everolimus, and sunitinib), hormonal therapies [somatostatin analogs (octreotide or lanreotide)] and the novel peptide receptor radionuclide therapy. Nevertheless, all these therapeutic modalities show only minimal response in patients with PNETs in the clinic. Therefore, novel targets need to be identified that could improve the dismal outcome of advanced PNETs. An analysis of PNET tissue identified p21-activated Kinase 4 (PAK4) and nicotinamide Phosphoribosyltransferase (NAMPT) as two new therapeutic targets. PAK4 is the downstream effector of Rac1 (members of the Rho family of GTPases) and is involved in critical cellular processes such as cell motility, proliferation, and survival. More importantly, PAK4 protein has been implicated in the activation of Ras/Raf/Mek/Erk and PI3K/Akt/mTOR signaling in cancers. Similarly, NAMPT is an enzyme that catalyzes the rate-limiting step in the principal salvage pathway of NAD biosynthesis in mammals. Tumor cells have highly active glycolytic, pentose and fatty acid synthesis pathways that require persistent high levels of NAD. Consequently, most cancers rely more heavily on NAMPT for rapid NAD biosynthesis. Earlier we demonstrated that biological or chemical inhibition of PAK4-NAMPT by RNAi or by a dual inhibitor (KPT-9274 a Phase I drug and its analogs) can suppress PNET proliferation and reduce the growth of subcutaneous xenografts. Our new studies show that PAK4-NAMPT dual inhibition can suppress PNET anchorage independent growth and metabolomic analysis of KPT-9274 treated PNET cells revealed significant alterations in a series of metabolites related to NAD signaling. KPT-9274 synergistically enhanced the anti-tumor activity of everolimus (combination index <1). Molecular analysis of combination treatment showed down-regulation of known everolimus resistance drivers including mTORC1, mTORC2, PI3K, ERK, FAK, RICTOR, ß-catenin. Importantly, combination treatment of KPT-9274 (150mg/kg) and everolimus (2.5 mg/kg used at sub-optimal dose) caused reduction of PNET xenografts. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNETs that warrant further clinical investigations.

Citation Format: Gabriel B. Mpilla, Amro Aboukameel, Md Hafiz Uddin, Mohammed N. Al-Hallak, Bayan Al-Share, Yosef Landesman, Yiwei Li, Steve Kim, Rafic Beydoun, Ramzi M. Mohammad, Philip A. Philip, Bassel El-Rayes, Asfar S. Azmi. Novel targets for therapy resistant pancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1122.