Pancreatic cancer is a highly chemo-resistant tumor type known to aggressively metastasize at an early stage with an overall five-year survival rate of ~6%. In this study we tested the efficacy of ONC201 and ONC212 in a panel of pancreatic cancer cell lines and patient-derived models in vitro and in vivo. ONC201 is the founding member of the imipridone class of small molecules with anti-proliferative and pro-apoptotic effects in various tumor types. Kline et al. and Allen et al. previously showed that ONC201 stimulates the integrated stress response by up-regulating ATF4, CHOP and DR5 followed by induction of apoptosis by up-regulating TRAIL. While the spectrum of ONC201 efficacy is broad among tumor types, pancreatic cancer cells are relatively insensitive. ONC201 exhibits low micromolar GI50 values in 3 out of 7 pancreatic cancer cell lines and 2 out of 9 patient-derived cells that were most sensitive among the pancreatic cell lines and samples tested. ONC201 induces the integrated stress response in both ONC201-sensitive and –insensitive pancreatic cancer cell lines. Interestingly, ONC201-treated resistant cells arrest in G1 and do not go through apoptosis. In order to address insensitivity to ONC201 in pancreatic cancer we explored two approaches. The first approach included treating with the ONC201 analogue ONC212, an imipridone that is currently under pre-clinical development. In vitro and in vivo studies consistently show a higher potency of ONC212 as compared to ONC201 in pancreatic cancer, especially in ONC201-insensitive models. We are currently investigating the mechanism of action of ONC212 in comparison to ONC201. The second approach to address ONC201-insensitive pancreatic cancer was combination treatment with the IGF1-R inhibitor AG1024. Western blot analysis of receptor tyrosine kinase expression levels in the panel of pancreatic cancer cell lines revealed a strong correlation between resistance to ONC201 and high expression of IGF1-R. Therefore we hypothesized that IGF1/IGF1-R might play a role in the resistance of pancreatic cancer cells to ONC201. Indeed, treatment of resistant pancreatic cancer cells with the IGF1-R inhibitor AG1024 sensitized the cells to ONC201. We are currently further exploring the involvement of IGF1-R in the ONC201 resistance mechanism. Furthermore, in-vivo studies are ongoing to validate the efficacy of the combination treatment. In summary, although pancreatic cancer is known to be refractory to many drugs, this study introduces two different approaches with imipridone small molecules ONC212 and ONC201 that show promising therapeutic potential for pancreatic cancer.
Citation Format: Avital Lev, Amriti R. Lulla, Jessica Wagner, David T. Dicker, Wafik S. El-Deiry. Anti-cancer efficacy of imipridones in pancreatic cancer: single agent ONC212 or combination of ONC201 with IGF1-R inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1067. doi:10.1158/1538-7445.AM2017-1067