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Lev A, Lulla AR, Wagner J, Ralff MD, Kiehl JB, Zhou Y, Benes CH, Prabhu VV, Oster W, Astsaturov I, Dicker DT, El-Deiry WS
Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP
Oncotarget (2017) 8:81776-81793.
Abstract
Pancreatic cancer is chemo-resistant and metastasizes early with an overall five-year survival of similar to 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 (N = 16 including 9 PDX-cell lines). We demonstrate ONC212 efficacy in 4 in-vivo 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 in vivo. 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.
Note
Publication Date: 2017-10-01.
PMCID: PMC5669847
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Last updated on Saturday, August 22, 2020