Abstract 6122: Targeting mutant p53 and KRAS for novel pancreatic cancer therapy by combination treatment of simvastatin and imipridones
Authors: Tian Xiaobing , Deiry Wafik S. 
Published: April 2023

KRAS mutation is found in 95% pancreatic ductal adenocarcinoma (PDAC). TP53 is altered in 70% of patients with PDAC that co-occur with KRAS mutations. Enhanced de novo cholesterol biosynthesis is a hallmark of cancer cells. P53 inhibits the mevalonate pathway to mediate tumor repression. p53 mutations drive de novo cholesterol pathway activation and are required for the proliferation of KRAS-mutant cancers. Inhibition of the mevalonate pathway leads to feedback activation of SREBP-2, which restores mevalonate pathway and leads to re-activation of KRAS and restoration of mutant p53 GOF. Imipridones induced ATF4 through the action of mitochondria protease ClpP. Simvastatin triggers ATF4 activation through inhibition of mevalonate pathway. We hypothesize that combined treatment with imipridones can overcome the resistance to simvastatin by two different mechanisms: (1) Imipridones inhibit oxidative phosphorylation through ClpP hyperactivation and result in AMPK activation. AMPK phosphorylates and inhibits SREBP-2 transcriptional function, which blocks the feedback activation of SREBP-2. (2) Enhanced ATF4 and CHOP induction through different pathways leads to cancer cell death. We also expect that the combined treatment through sustained induction of ATF4 and CHOP can sensitize cancer cells to imipridone treatment.

Mouse and human PDAC cell lines (KPCY, HPAF-II, and PANC-1) with p53 and KRAS mutations were used to test the effects of combination treatment of simvastatin and imipridones. The combined treatments synergistically inhibited the proliferation of p53 and KRAS co-mutant cell lines. For example, the synergy scores of simvastatin and ONC201 combination are 75 (KPCY), 15 (HPAF-II), and 14 (PANC-1). Enhanced cell death is consistent with sustained and enhanced induction of ATF4 and CHOP compared to single drug treatment alone. Imipridones activated AMPK in the tested PDAC cell lines. Imipridones potently inhibit AKT and ERK1/2 activation at 72-hour time point, which might also contribute to block above mentioned feedback activation of KRAS. We also observed that cell lines with a structural mutant of p53 are more sensitive to the combination treatments than a cell line with a DNA-contact mutant of p53, which is consistent with the fact that simvastatin treatment leads to degradation of structural p53 mutants. Surprisingly, our data indicated that simvastatin potently inhibits kinase WEE1 and leads to CDK1 dephosphorylation and activation, which has not been reported before. Together, our data is consistent with publications that p53 mutated cancer cell lines are sensitive to statin treatments. In short, combination treatment may overcome simvastatin resistance and/or imipridone resistance by modulating ATF4/CHOP and SREBP-2 activity.

Citation Format: Xiaobing Tian, Wafik S. Deiry. Targeting mutant p53 and KRAS for novel pancreatic cancer therapy by combination treatment of simvastatin and imipridones [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6122.