Abstract B41: Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors

Abstract

Abstract E-cadherin (CDH1) is a cell-cell adhesion protein implicated in the epithelial-mesenchymal transition and frequently dysregulated in diffuse gastric cancer (DGC) and invasive lobular breast cancer (ILBC). Germline CDH1 mutations define hereditary diffuse gastric cancer (HDGC), a rare cancer syndrome characterised by highly penetrant DGC and an elevated rate of ILBC in females. There is a strong need to develop specific chemopreventative strategies for CDH1 germline mutation carriers which are capable of reducing the viability of early stage CDH1-deficient cancers whilst minimizing side effects. We have previously applied a synthetic lethal approach to an isogenic pair of MCF10A breast cell lines, one with and one without functional CDH1 expression (MCF10A CDH1-/-), to screen for drugs which preferentially reduce the viability of CDH1-deficient cells. This led to our finding that histone deacetylase inhibitors (HDACi; entinostat and vorinostat) and SRC inhibitors (SRCi; saracatinib) are involved in synthetic lethal interactions with MCF10A CDH1-/- cells. Single agent therapy, however, only produces a modest synthetic lethal effect, leading to our interest in developing synergistic drug combinations. We have now shown that statins, inhibitors of the HMG-CoA reductase enzyme, also show a synthetic lethal phenotype in the MCF10A isogenic cell line pair. This result suggests that survival of E-cadherin-deficient cells may be enhanced by the mevalonate pathway, a metabolic pathway responsible for synthesizing prenyl groups and subsequently activating the small GTPase proteins Rho, Rac, and Cdc42. SRC is also a known activator of GTPase proteins and combined statin and saracatinib treatment caused an enhanced reduction in cell viability in the isogenic MCF10A cells whilst maintaining the synthetic lethal phenotype. This drug combination was shown to be synergistic in both cell lines using the Chou-Talalay median effect analysis and is the first known example of synergy between a statin and SRC inhibitor. Combined statin and HDACi treatment also enhanced cell viability inhibition and was synthetic lethal in the MCF10A pair. This effect was observed using both class-I specific (entinostat) and pan- (vorinostat) HDACi and was synergistic in both cell lines using median effect analysis. These are the first known examples of synergistic drug combinations being used in the field of synthetic lethality and serve as a foundation for novel DGC and ILBC treatment options. Citation Format: Andrew Single, Augustine Chen, Bryony Telford, Henry Beetham, Parry Guilford. Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B41.