Abstract 4803: A novel class of phenylacrylonitrile-based small molecules selectively induce double-strand DNA damage in breast cancer cells

Abstract

Abstract We have discovered a class of phenylacrylonitrile-based small molecules that selectively target breast cancer cell lines while having little to no effect on normal breast cancer cells or on cell lines derived from other tumour types including colon, ovarian, lung, skin, prostate and pancreatic carcinomas, neuroblastoma and glioblastoma. Indeed these molecules show more than 200-fold selectivity towards breast cancer cells compared with other tumour types, while maintaining nM potency, as determined by the MTT growth inhibition (GI50) assay with GI50 values of 0.2-2.0μM (72h exposure). Moreover, the sensitive breast cancer cell lines represent tumour types from the four main breast cancer classifications including ER+ luminal A (MCF-7, T47-D and ZR-75-1 cells), ER+ luminal B (BT-474), HER2+ (SKBR-3), and most importantly the Basal (triple negative MDA-MB-468 and BT20) classification which traditionally carries a very poor prognosis. Our novel class of molecules also retain activity in MCF-7/VP16 cells (GI50 0.2μM) which overexpresses the drug resistance ABCC1 gene. Only one breast cancer cell line has shown insensitivity, MDA-MB-231 (Basal triple negative), which unlike all of the other breast cell types has amplifying mutations in KRas and BRaf activity, a genotype found in less than 5% of breast cancer tumours. Furthermore, our novel compounds induce minimal effects on the growth of normal MCF10A breast cells. Analysis of our most sensitive breast cancer cell line (MDA-MB-468) shows a significant increase in gammaH2AX within 12h of exposure to our lead phenylacrylonitrile molecule, indicative of DNA double strand breakage. This response is concomitant with an increase in the phosphorylation of the cell cycle check point activator CHK2. Cell cycle analysis shows an increase in the proportion of cells in the S-phase of the cell cycle within 24h of exposure, concomitant with a decrease in the proportion of cells in the G1-phase, and preceding an increase in the sub-G1 cell death population. The ability to specifically target breast tumours, while having little or no effect on normal breast cells, or other tumour types is a unique finding. Elucidating the mechanism controlling this phenomenon is now the focus of our research efforts. Citation Format: Jennette A. Sakoff, Jayne Gilbert, Geoff De Iuliis, Adam McCluskey. A novel class of phenylacrylonitrile-based small molecules selectively induce double-strand DNA damage in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4803.