Abstract B143: HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models
Authors: Ferretti Stephane , Jaco Isabel , Decker Andrea , Hemmerlin Christelle , Scheufler Clemens , Quadt Cornelia , Sterker Dario , Gavioli Elena , Nunez Eloisa Jimenez , Dammassa Ernesta , Schaeffer Fanny , Albrecht Genevieve , Clementi Giorgia , Martus Hansjoerg , Hamon Jacques , Hinrichs Juergen , Laborde Laurent , Dourdoigne Marion , Moschetta Michele , Stump Ramona , Andraos-Rey Rita , Welly Sarah , Barbe Stephanie , Romanet Vincent , Reschke Markus , Kanter Ruben De , Jensen Michael , Moebitz Henrik , Cros Marta Cortes 
Published: December 2023

Abstract
Colorectal carcinoma (CRC) as well as other indications that have lost competence in mismatch repair and have a phenotype known as microsatellite instability (MSI), remain a significant unmet medical need. Large-scale functional genomics screens across cell line panels have identified the Werner Syndrome RecQ helicase (WRN) as being synthetic lethal with MSIhigh cancers. Thus, WRN inhibitors may offer a new therapeutic avenue in MSIhigh cancers. We report the preclinical characteristics of HRO761, a first-in-class, highly potent and selective inhibitor of WRN helicase, with optimized drug-like properties. We evaluated the pharmacokinetics and pharmacodynamics of HRO761 when administered orally once daily in MSIhigh and also assessed the efficacy as single agent across cell (CDX) and patient-derived (PDX) xenografts as well as in combination with irinotecan, a prodrug derivative of camptothecin which acts as topoisomerase I inhibitor. Daily oral administration of HRO761 was highly efficacious across the CDX and PDX models evaluated with a disease control rate of 70% across all indications. In the SW48 CDX model, tumor regression was sustained for 2 months at the highest dose followed by slow relapse. HRO761 also induced WRN degradation, activated the DNA damage response and induced p53 target genes in a dose dependent manner. In vitro combination with irinotecan deepened sensitivity to HRO761 with a more sustained response in MSIhigh CRC cell lines. Combining administration of HRO761 daily with irinotecan weekly was highly efficacious and beneficial over single agent in CDX and PDX models. In CDX models, the combination showed a robust benefit, translating into homogeneous, sustained regression leading to a dose-dependent tumor growth delay even after treatment discontinuation. Overall, we demonstrate that the novel, selective, first-in-class WRN inhibitor HRO761 is a promising therapeutic approach for the treatment of MSIhigh cancer patients either as single agent or in combination with irinotecan. Clinical development is currently ongoing to assess the safety, tolerability and preliminary anti-tumor activity in patients with MSIhigh colorectal cancer and other MSIhigh solid tumors [clinicaltrials.gov NCT05838768].
Citation Format: Stephane Ferretti, Isabel Jaco, Andrea Decker, Christelle Hemmerlin, Clemens Scheufler, Cornelia Quadt, Dario Sterker, Elena Gavioli, Eloisa Jimenez Nunez, Ernesta Dammassa, Fanny Schaeffer, Genevieve Albrecht, Giorgia Clementi, Hansjoerg Martus, Jacques Hamon, Juergen Hinrichs, Laurent Laborde, Marion Dourdoigne, Michele Moschetta, Ramona Stump, Rita Andraos-Rey, Sarah Welly, Stephanie Barbe, Vincent Romanet, Markus Reschke, Ruben De Kanter, Michael Jensen, Henrik Moebitz, Marta Cortes Cros. HRO761, a first-in-class, clinical stage WRN inhibitor with potent preclinical anti-tumor activity in MSIhigh models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B143.