TY - JOUR
T1 - E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer
AU - Bajrami, Ilirjana
AU - Marlow, Rebecca
AU - van de Ven, Marieke
AU - Brough, Rachel
AU - Pemberton, Helen N.
AU - Frankum, Jessica
AU - Song, Feifei
AU - Rafiq, Rumana
AU - Konde, Asha
AU - Krastev, Dragomir B.
AU - Menon, Malini
AU - Campbell, James
AU - Gulati, Aditi
AU - Kumar, Rahul
AU - Pettitt, Stephen J.
AU - Gurden, Mark D.
AU - Cardenosa, Marta Llorca
AU - Chong, Irene
AU - Gazinska, Patrycja
AU - Wallberg, Fredrik
AU - Sawyer, Elinor J.
AU - Martin, Lesley-Ann
AU - Dowsett, Mitch
AU - Linardopoulos, Spiros
AU - Natrajan, Rachael
AU - Ryan, Colm J.
AU - Derksen, Patrick W.B.
AU - Jonkers, Jos
AU - Tutt, Andrew N.J.
AU - Ashworth, Alan
AU - Lord, Christopher J.
PY - 2018/4/4
Y1 - 2018/4/4
N2 - 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
AB - 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
U2 - 10.1158/2159-8290.CD-17-0603
DO - 10.1158/2159-8290.CD-17-0603
M3 - Article
SN - 2159-8274
VL - 8
SP - 498
EP - 515
JO - Cancer discovery
JF - Cancer discovery
IS - 4
ER -