The E-cadherin (CDH1) tumour suppressor gene encodes a calcium-dependent cell-cell adhesion glycoprotein, which has roles in maintaining cell polarity, differentiation, cell migration and survival. E-cadherin dysfunction is a feature common to many epithelial tumours, with the highest incidence occurring in diffuse gastric cancer (50%) and lobular breast cancer (63%) and can occur via CDH1 mutation, deletion or epigenetic silencing. Although E-cadherin dysfunction is relatively common, precision medicine approaches that exploit this pathogenic alteration are not yet available. Using genetic and small-molecule perturbation screens in breast tumour cells with CRISPR-Cas9 engineered CDH1 mutations, we identified a synthetic lethal interaction between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Using data from large-scale genetic screens in molecularly diverse breast tumour cell lines, we found that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin defective cells, phenotypes that were associated with a defect in cytokinesis and aberrant p120-catenin phosphorylation and localisation. In vivo, ROS1 inhibitors produced profound anti-tumour effects in multiple, distinct, models of E-cadherin defective breast cancer. This data therefore provides the pre-clinical rationale for assessing ROS1 inhibitors such as the licensed drug crizotinib in appropriately stratified patients.

Citation Format: Ilirjana Bajrami, Rebecca Marlow, Marieke van de Ven, Rachel Brough, Helen N. Pemberton, Jessica Frankum, Fei Fei Song, Rumana Rafiq, Asha Konde, Malini Menon, James Campbell, Aditi Gulati, Rahul Kumar, Stephen J. Pettitt, Mark D. Gurden, Marta Llorca Cardenosa, Irene Chong, Patrycja Gazinska, Fredrik Wallberg, Elinor J. Sawyer, Lesley-Ann Martin, Mitch Dowsett, Spiros Linardopoulos, Colm Ryan, Patrick W. Derksen, Jos Jonkers, Andrew N.J. Tutt, Alan Ashworth, Christopher J. Lord. E-cadherin/ROS1 inhibitor synthetic lethality in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2986.