Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP

• Published in: Oncotarget 2017-10, Vol.8 (47), p.81776-81793
• Main Authors: Lev, Avital, Lulla, Amriti R, Wagner, Jessica, Ralff, Marie D, Kiehl, Joshua B, Zhou, Yan, Benes, Cyril H, Prabhu, Varun V, Oster, Wolfgang, Astsaturov, Igor, Dicker, David T, El-Deiry, Wafik S
• Format: Article
• Language: English
• Subjects: Priority Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.20819

Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of ∼8.2%. First-in-class imipridone ONC201 is a small molecule in clinical trials with anti-cancer activity. ONC212, a fluorinated-ONC201 analogue, shows preclinical efficacy in melanoma and hepatocellular-cancer models. We investigated efficacy of ONC201 and ONC212 against pancreatic cancer cell lines ( =16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 models including ONC201-resistant tumors. ONC212 is active in pancreatic cancer as single agent or in combination with 5-fluorouracil, irinotecan, oxaliplatin or RTK inhibitor crizotinib. Based on upregulation of pro-survival IGF1-R in some tumors, we found an active combination of ONC212 with inhibitor AG1024, including . We show a rationale for targeting pancreatic cancer using ONC212 combined with targeting the unfolded-protein response and ER chaperones such as GRP78/BIP. Our results lay the foundation to test imipridones, anti-cancer agents, in pancreatic cancer, that is refractory to most drugs.