E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer
- 1 April 2018
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 8 (4), 498-515
- https://doi.org/10.1158/2159-8290.cd-17-0603
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. 371Other Versions
This publication has 51 references indexed in Scilit:
- Synthetic lethality of PARP and NAMPT inhibition in triple‐negative breast cancer cellsEMBO Molecular Medicine, 2012
- The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivityNature, 2012
- ChimeraScan: a tool for identifying chimeric transcription in sequencing dataBioinformatics, 2011
- Functional Viability Profiles of Breast CancerCancer Discovery, 2011
- Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in miceDisease Models & Mechanisms, 2011
- Significance of E-cadherin expression in triple-negative breast cancerBritish Journal of Cancer, 2010
- Cadherins and cancer: how does cadherin dysfunction promote tumor progression?Oncogene, 2008
- Loss of p120 catenin and links to mitotic alterations, inflammation, and skin cancerProceedings of the National Academy of Sciences of the United States of America, 2008
- The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membraneExperimental Cell Research, 2008
- Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancerProceedings of the National Academy of Sciences of the United States of America, 2007