Abstract P6-03-15: Inhibition of breast cancer tumor cell lines by simvastatin is dependent on specific p53 mutation

Background: Simvastatin is an HMG-CoA reductase inhibitor widely used to treat cardiovascular diseases. In retrospective studies, statin treatment has been associated with a modest decrease in overall cancer incidence, including breast cancer (10-15%). Simvastatin Inhibited the PI3K/Akt/mTOR pathway in a pilot window-of-opportunity trial in neoadjuvant breast cancer. Mutation in TP53 is correlated with elevated expression of genes regulating cholesterol biosynthesis and sensitivity to statin treatment in vitro. We hypothesized that specific mutations in TP53 would be associated with differential sensitivity to simvastatin. Method: We generated MCF10A stably transduced cell lines over-expressing ten frequent TP53 missense point mutations. We assessed the impact of TP53 mutation on growth inhibition induced by simvastatin treatment (range of 1-30 µM for 96 hrs). In parallel, induction of apoptosis was measured by caspase3 reporter assay. Illumina 4-plexed 1x50bp RNA sequencing was performed on cells with R273H, G245S, R248Q, Y234C and wt TP53 before and after exposure to 2.5 µM simvastatin. Results: We confirmed that mutation in TP53 was markedly associated with growth inhibition by simvastatin treatment in vitro. We now demonstrate that TP53 mutation in R273C, G245S and R273H are highly sensitive to simvastatin with IC50 values ≤ 2.1 µM. In contrast, TP53 mutations in Y234C and R248Q were approximately five-fold more resistant. The resistant mutations were similar to MCF10A overexpressing wild type TP53. Growth inhibition was correlated with induction of apoptosis, and could be rescued by addition of farnesylpyrpphosphate and geranylgeranylpyrophosphate. HMGCR upregulation was observed across all treated cell lines. RNA-seq analysis confirms down regulation of the PIK3CA, PIK3CB, and Akt in the sensitive cell lines, but paradoxical upregulation in the resistant cells. Further gene expression analysis will be presented. Conclusion: Specific TP53 mutation status may impact sensitivity of breast cancer to simvastatin treatment. Citation Format: Ferdosi SR, Grewal H, Gonzalez-Malerva L, Eaton S, Briones N, LaBaer J, Anderson KS. Inhibition of breast cancer tumor cell lines by simvastatin is dependent on specific p53 mutation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-15.