Abstract 6225: Addition of TRAIL receptor agonists after treatment with ONC201 or ONC212 converts pancreatic cancer cells from anti-proliferative to apoptotic in vitro

Abstract

Abstract The 7% five-year survival rate for pancreatic cancer patients has remained unchanged for decades; the need for novel therapeutic interventions is imminent. ONC201 is the founding member of the impridone class, a class of orally bioavailable small molecules which show efficacy in multiple tumor types. ONC201 and ONC212, a fluorinated imipridone, have been shown to be potent inducers of the tumor necrosis factor related apoptosis inducing ligand (TRAIL) pathway. Both compounds are currently in clinical trials. In the context of pancreatic cancer, ONC201 and ONC212 induce either apoptotic or anti-proliferative effects. Additionally, both compounds activate the integrated stress response leading to DR5 upregulation in various cell types. We hypothesized that exogenous addition of TRAIL receptor agonists after pre-treatment with ONC201 or ONC212 could convert cells from anti-proliferative to apoptotic. Here, we examined both rhTRAIL and TLY012, a novel TRAIL receptor agonist with a substantially improved half-life. Pancreatic cancer cell lines were screened for synergy when treated with ONC201 or ONC212 for 72 hours followed by either rhTRAIL or TLY012 for 4 hours. Four cell lines (AsPC-1, BxPC3, Capan-1, and PANC-1) showed potent synergy with both rhTRAIL and TLY012. Growth inhibition was assessed through both Cell-Titer Glo and colony assays. Apoptotic synergy was determined using Cell-Titer Glo, western blots for PARP cleavage, and sub-G1 flow cytometric assays. Further analysis showed that ONC201 activates the integrated stress response and primes pancreatic cancer cells for TRAIL-induced apoptosis through regulation of key proteins. Upregulation of the integrated stress response and downregulation of XIAP, c-FLIP, and Bcl-XL was observed after treatment with ONC201 in BxPC3 and PANC-1 cell lines. The combination of ONC201 and TRAIL receptor agonists was non-toxic to human foreskin fibroblasts. Future experiments aim to examine G1 arrest after treatment with ONC201 and ONC212 via western blot and flow cytometry, to confirm surface expression of TRAIL and DR5 via flow cytometry, and to determine efficacy in pancreatic cancer xenografts. Taken together, these data indicate a novel therapeutic strategy for treatment of patients with ONC201 and ONC212 resistant pancreatic tumors. Citation Format: Aakash V. Jhaveri, Lanlan Zhou, Isacco Ferarrini, Young Lee, Wafik S. El-Deiry. Addition of TRAIL receptor agonists after treatment with ONC201 or ONC212 converts pancreatic cancer cells from anti-proliferative to apoptotic in vitro [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6225.