E-cadherin deficiency a novel determinant of ROS1 inhibitor sensitivity

Ilirjana Bajrami1,Stephen Pettitt1,Rachel Brough1,Helen Pemberton1,Jessica Frankum1,James Campbell1,Alan Ashworth2,Christopher Lord1

1ICR, LONDON, UK,2UCSF, SAN FRANCISCO, USA

Presenting date: Tuesday 3 November
Presenting time: 16.10-16.25

Background

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 (56%) and can occur via CDH1 mutation, deletion or epigenetic silencing. Although E-cadherin dysfunction is relatively common, approaches to target this pathogenic alteration do not as yet exist.

Method

We have taken an integrated functional genomics approach to identifying E-cadherin synthetic lethality effects that exploits siRNA. Using a combination of Achilles’ Heel siRNA screens in histologically and genetically diverse tumour cell line panels, we have identified a compendium of genes whose disruption selectively targets E-cadherin deficient cells. Alongside the Achilles’ Heel screens in tumour cell models, complementary screens siRNA and pharmacological screens in isogenic systems with Zinc-finger and CRISPR-engineered E-Cadherin defects were undertaken.

Results

The integrated functional genomics approach identified a robust synthetic lethal interaction between the orphan receptor tyrosine kinase ROS1 and E-cadherin dysfunction. Functional and chemical inhibition of ROS1 in a variety of breast cell line models induced sensitivity in E-cadherin deficient cells.  The synthetic lethal interaction between E-cadherin and ROS1 was characterized by induction of apoptosis, nuclear defects, and a G2/M cell cycle arrest. 

Conclusion

This integrated genomics approach identified novel genetic determinants selective for E-cadherin deficiency, a gene that is recurrently mutated in breast cancer.  This study suggests that E-cadherin deficiency could be used as candidate predictive biomarker in future clinical trials involving ROS1 inhibitors.