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Cancer Discov. 2018 Apr;8(4):498-515. doi: 10.1158/2159-8290.CD-17-0603.

E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer.

Author information

1
The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
2
Cancer Research UK Gene Function Laboratory, The Institute of Cancer Research, London, United Kingdom.
3
The Breast Cancer Now Research Unit, King's College London, London, United Kingdom.
4
Mouse Clinic for Cancer and Aging (MCCA) Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Biomedical Research Institute INCLIVA, Hospital Clinico Universitario Valencia, University of Valencia, Spain.
6
FACS Core Facility, The Institute of Cancer Research, London, United Kingdom.
7
Division of Cancer Studies, Guy's Hospital, King's College London, London, United Kingdom.
8
Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
9
Systems Biology Ireland, University College Dublin, Dublin, Ireland.
10
Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
11
Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
12
UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California. Chris.Lord@icr.ac.uk alan.ashworth@ucsf.edu.
13
The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Chris.Lord@icr.ac.uk alan.ashworth@ucsf.edu.

Abstract

The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established 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 associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients.Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin-defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

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