Industry Insights Seminar - Novartis - Targeting the WRN helicase in MSI cancers
The RecQ DNA helicase WRN was identified as a synthetic lethal target in MSIhigh tumors by several genetic screens. Despite recent advances in the treatment of MSIhigh tumors by immune checkpoint inhibitors, a significant proportion of patients still fails to respond to or relapses after single agent anti-PD1 or combination of anti-PD1 plus anti-CTLA4 treatments. We will present the biochemical, cellular and pharmacological characterization of the first potent and selective WRN helicase inhibitor, HRO761. We will show that HRO761 is an allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, thus locking WRN in an inactive conformation. We will further show that pharmacological inhibition of WRN by HRO761 recapitulates the phenotype observed by WRN genetic suppression, leading to activation of the DNA damage response and inhibition of tumor cell growth selectively in MSIhigh but not in MSS cells. In addition, we will show that WRN inhibition leads to WRN protein degradation only in MSIhigh tumor cells and give insights into the mechanism of WRN degradation upon DNA damage response induction. A phase 1 clinical trial with HRO761 is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with MSIhigh colorectal cancer and other MSIhigh solid tumors
Date:
12 June 2025, 12:00
Venue:
IMS-Tetsuya Nakamura Building, Roosevelt Dr, Headington OX3 7TY
Venue Details:
Ground Floor Seminar Room
Speaker:
Dr Marta Cortes-Cros (Novartis)
Organising department:
Divisional Office (MSD)
Organisers:
Elizabeth Covey-Crump (MSD Business Partnerships Office),
Sheena Lee (MSD Business Partnerships Office),
Medical Sciences Division Business Partnerships Office (University of Oxford)
Organiser contact email address:
sheena.lee@medsci.ox.ac.uk
Host:
Elizabeth Covey-Crump (MSD Business Partnerships Office)
Part of:
Industry Insight Seminar Series
Booking required?:
Required
Booking url:
https://forms.office.com/e/h3vKk0s5Yb
Cost:
Free
Audience:
Members of the University of Oxford and the Biotech/Pharma industry
Editor:
Sheena Lee
