Abstract B04: Synthetic lethal targeting of E-cadherin-deficient cancers

Abstract

Abstract Germline mutation of the E-cadherin gene (CDH1) genetically defines the inherited cancer syndrome hereditary diffuse gastric cancer (HDGC). HDGC is characterized by highly penetrant diffuse gastric cancer (DGC) and an elevated rate of lobular breast cancer (LBC). Somatic CDH1 mutations also occur frequently in the sporadic forms of these cancers. We propose that the loss of E-cadherin, a tumor suppressor gene, creates vulnerabilities in the cancer cell that can be exploited with drugs (“synthetic lethal” interactions). We are particularly interested in identifying drugs that can be used for the chemoprevention of advanced disease in HDGC family members by targeting the multifocal precursor lesions that occur in stomach and breast tissue. In the stomach, these early lesions are mucosally-confined stage T1a signet ring cell carcinomas. Up to 400 independent foci have been identified in the stomachs of CDH1 mutation carriers; these foci are genetically homogenous and are likely to only require the 2nd CDH1 hit for their initiation. To identify the vulnerabilities created by E-cadherin loss, we have conducted a genome-wide siRNA knockdown screen, a 4000 compound known drug screen and a 114,000 compound library screen in isogenic MCF10a breast cell lines with and without E-cadherin expression. The functional screen has shown that GPCR signaling proteins are highly enriched amongst the candidate synthetic lethal proteins, as well as many protein classes associated cell signaling and cytoskeletal function. Drugs that show increased activity against the E-cadherin-deficient cells include the JAK inhibitor LY2784544, the c-SRC inhibitor saracatanib, the beta-2 adrenoreceptor (GPCR) agonist formoterol, several HDAC inhibitors and statins. Detail on synergistic combinations involving many of these drugs is provided in the abstract entitled “Statins show synthetic lethality in E-cadherin-deficient cells and are synergistic with SRC and HDAC inhibitors”. To identify mechanisms associated with E-cadherin synthetic lethality, we used the cell viability data from the siRNA screen to examine the distributions of cell viabilities for the genes that make up the major KEGG signaling pathways. Using the Kolomogorov-Smirnof method to test for significance, we identified the PI3K-AKT survival pathway as being central to E-cadherin's synthetic lethal associations. These findings pave the way for the development of rationally designed drug combinations for the chemoprevention and treatment of E-cadherin-negative cancers. Citation Format: Parry J. Guilford, Augustine Chen, Bryony Telford, Andrew Single, Henry Beetham, Tanis Godwin. Synthetic lethal targeting of E-cadherin-deficient cancers. [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 B04.