Cancer Research · 2025
T. Yap、Natalie Cook、Elisa Fontana 等
WRN is an enzyme critical for DNA repair and genome stability and is a promising synthetic lethal target for MSI cancers. 40-70 % of patients (pts) with MSI/dMMR solid tumors do not respond to immune checkpoint inhibitors (ICI) or develop resistance, representing an unmet need in MSI cancers. RO7589831 is a novel first-in-class covalent, irreversible WRN inhibitor that induces dose-dependent DNA damage and tumor growth inhibition in MSI preclinical models, supporting its clinical evaluation in MSI pts.
This open-label, multi-center, FIH study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of RO7589831 in pts with MSI and/or dMMR advanced solid tumors (NCT06004245). The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). 14 paired tumor biopsies were collected for translational analysis.
As of Nov 25, 2024, 44 pts (24 F, 20 M; median age 62y (32-77y)) were enrolled in six dose cohorts at RO7589831 daily doses from 150 mg to 2000 mg. Based on clinical first dose PK data (rapid absorption, mean Tmax 2.6 h [± 1.3h] and half-life 4.4 h [±1.8h], n=41), RO7589831 was dosed orally once (QD) or twice (BID) daily. Among the 44 pts (22 colorectal (CRC) and 22 non-CRC), median prior treatment lines were 3 (range 1-12); 89% had received ICIs. 35 pts had MSI tumors (18 CRC and 17 non-CRC). No dose-limiting toxicities (DLTs) have been reported and the MTD has not been reached. The most common treatment-emergent AEs across all doses were nausea (52.3%), diarrhea (34.1%), and vomiting (31.8%). Grade (G)3 treatment related AEs (TRAE) were nausea and increased AST/ALT in 2 pts each (4.3%) as well as fatigue and anemia in 1 pt each (2.1%). No G4 or worse TRAEs were observed. Of the efficacy evaluable MSI pts (n= 32), four RECISTv1.1 partial responses (PRs) (2 confirmed and 2 ongoing unconfirmed PRs) were observed in post-ICI-treated MSI CRC (n=1), ovarian (n=1), and endometrial cancer (n=2) for up to 9.5+ mths. Disease control rate (DCR) was 68.8% (95%CI 51.13, 86.37) and 20 (62.5%) pts achieved RECISTv1.1 stable disease (SD). 48.4% (15/31) of FDG-PET scan evaluable pts across all dose levels showed metabolic responses to RO7589831. All pts with RECIST PR showed pronounced metabolic responses (-50% to -90%). ctDNA molecular responses were observed in 2/2 pts with RECISTv1.1 PR, 8/9 pts with SD and 0/5 pts with disease progression.
RO7589831 is generally safe and well tolerated, with promising DCR, durable RECISTv1.1, FDG-PET metabolic and ctDNA molecular responses in pts with advanced MSI cancers, including ICI-treated pts, providing the first early clinical proof-of-concept for effectively drugging WRN. Dose optimization cohorts are ongoing to establish the RP2D.
Timothy A. Yap, Natalie Cook, Elisa Fontana, Erica S. Tsang, Oliver Bechter, Marwan Fakih, Kristoffer S. Rohrberg, Emiliano Calvo, Elena M. Elez, Meredith Pelster, John H. Strickler, Ignacio Matos, Adam Sharp, Sophia Blake, David Dejardin, Stephen Fowler, Nina Henkel, Michael Hettich, Angelika Lahr, Ting Liu, Christophe Meille, Piergiorgio Pettazzoni, Denise Reeves, Barbara Romagnoli, Sotirios Sotiriou, Daniel Waterkamp, Yali Fu, Sophie Postel-Vinay. First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT016.
Ageing research reviews · 2016
Junko Oshima、Julia M Sidorova、Raymond J Monnat
Werner syndrome (WS) is a prototypical segmental progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related progeroid syndromes.
Cancer Research · 2025
V. Samnotra、N. Ramos-Hernandez、Thomas H. Faitg 等
Werner syndrome helicase (WRN) is a RecQ helicase family member that plays an important role in genome stability, primarily through its involvement in DNA repair processes such as nonhomologous end-joining and homologous recombination. Upregulation of WRN in mismatch repair (MMR)-deficient or microsatellite instability-high (MSI-H) tumor cells facilitates DNA damage repair and, thus, cell survival. In these cells, WRN inhibition induces double-strand DNA breaks, leading to cell death. Therefore, WRN has emerged as a novel, promising synthetic lethality target in MMR-deficient/MSI-H solid tumors, particularly endometrial and colorectal cancers, which exhibit MMR-deficiency/MSI-H in approximately 20%-30% and 5%-15% of cases, respectively. GSK4418959, a WRNi, is a distinct, oral small molecule that uniquely binds to an allosteric site in the WRN helicase domain, exhibiting synthetic lethality in MMR-deficient/MSI-H tumor cells. It showed potent antitumor activity in in vitro and in vivo preclinical models by selectively inducing DNA damage and, consequently, death of MSI-H cancer cells.
The SYLVER first-in-human, open-label, multicenter, phase 1/2 trial (NCT06710847) opened on December 9, 2024 and aims to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK4418959, as monotherapy or in combination with a programmed cell death protein-1 (PD-1) inhibitor. The trial comprises WRNi monotherapy dose escalation (part 1), WRNi monotherapy dose expansion (part 2), and dose escalation of WRNi + PD-1 inhibitor (part 3). Key eligibility criteria include age ≥18 years, an advanced MMR-deficient/MSI-H solid tumor, an ECOG PS score of 0-1, and having exhausted standard of care (parts 1 and 3) or received 1-3 lines of systemic therapy, including ≥1 immune checkpoint inhibitor therapy (part 2). Patients who have not recovered from treatment-associated adverse events, have uncontrolled hypertension, or have received prior treatment with a WRNi are ineligible. Primary endpoints are safety during the dose-limiting toxicity observation period (ie, first 21 days; parts 1 and 3) and objective response rate (part 2). Secondary endpoints include overall safety (parts 1-3), pharmacokinetics (parts 1-3), progression-free survival (part 2), and duration of response (part 2). Tumor responses will be assessed per RECIST 1.1. Planned enrollment is approximately 133 patients in the US, Australia, Japan, South Korea, Spain, Belgium and the Netherlands, with potential to expand to additional countries for later stages of the study.
This study (NCT06710847) is sponsored by GSK.
NCT06710847
Third-party medical writing support: Writing and editorial support, funded and coordinated by GSK, was provided by Tafara T.R. Kunota, PhD, and Mary C. Wiggin of Ashfield MedComms, an Inizio company.
Vivek Samnotra, Natalia Ramos-Hernandez, Thomas Faitg, Meenakshi Srinivasan, Tania Roy, Andrew Liu, Tomasz Zaremba, Clare Holford, Rachel Smith, Jason T. Henry, Jeanne Tie, Noboru Yamamoto, Gul Serbest. First-in-human, phase 1/2 study of GSK4418959, an oral Werner DNA helicase inhibitor, alone or combined with other anticancer agents in adults with advanced mismatch repair-deficient or microsatellite instability-high solid tumors (SYLVER) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT194.
Biochimica et biophysica acta. Molecular cell research · 2023
Benjamin R Jordan、Yujia Zhai、Zhi Li 等
Our study maps the classic nuclear localization signal (cNLS) domain within WRNIP that directs the protein's nuclear positioning.
Molecular Cancer Therapeutics · 2025
C. Lemech、Timothy Humphries、Tiago Biachi de Castria 等
Patients with advanced or metastatic solid tumors harboring microsatellite instability high (MSI-H) or DNA mismatch repair deficiency (dMMR) alterations have benefited from immune check point inhibitors (ICIs). However, many patients show innate or acquired resistance to ICIs. Therefore, additional therapies with rapid response rates and longer durations of response are needed. Tumors with MSI-H or dMMR alterations rely heavily on DNA repair mechanisms to avoid apoptosis and may respond well to inhibition of Werner RecQ like helicase (WRN), a protein with a critical role in DNA replication and repair. WRN activity is required for successful DNA replication at expanded thymine and adenine (TA) dinucleotide repeats occurring from dMMR. Loss of WRN leads to DNA damage at TA repeat sites, resulting in cell death and tumor regression. MOMA-341 is a potent and selective oral inhibitor of WRN that has demonstrated antitumor activity in dMMR/MSI-H models. DNA damage and anti-tumor activity are enhanced when MOMA-341 is combined with standard chemotherapies (eg, irinotecan). The selective activity of MOMA-341 supports its development as monotherapy or combination therapy for treatment of dMMR/MSI-H solid tumors.
This Phase 1, multi-center, open-label, dose escalation and dose optimization study is designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary anti-tumor activity of MOMA-341 in patients with MSI-H/dMMR alterations (NCT06974110). The monotherapy dose escalation phase (Arm 1A) will determine the presumptive optimal biological dose (OBD) and maximum tolerated dose (MTD); the dose optimization phase (Arm 1B) will assess safety, tolerability, PK, PDx, and antitumor activity of MOMA-341. Combination treatment arms with chemotherapy (e.g., irinotecan, Arm 2) or immunotherapies (Arm 3) will determine the presumptive OBD and MTD. Inclusion criteria are patients aged ≥18 years with histologically confirmed MSI-H/dMMR alterations, unresectable advanced or metastatic solid tumors, an Eastern Cooperative Oncology Group Performance Status ≤2, and those who have previously received and progressed on an anti-PD-L1 (USA) or who have been treated with anti-PD-L1 if approved/accessible (ex-USA). Participants are planned to enroll from centers across North America, Australia, and Europe. Primary endpoints include adverse events (AEs), dose-limiting toxicities, serious AEs, and/or AEs leading to discontinuation. Secondary endpoints include determination of the optimal Phase 2 dose; plasma PK parameters of MOMA-341 monotherapy and in combination with irinotecan or immunotherapies; and clinical activity assessments. Changes in DNA damage markers, covalent ligation of WRN by MOMA-341, and ctDNA responses will be assessed as exploratory endpoints. TA repeat expansions will be measured to further refine patient stratification biomarkers. Study sites are currently open and recruiting.
Charlotte Lemech, Timothy Humphries, Tiago Biachi de Castria, Andrea Cercek, Michael Overman, Shivaani Kummar, Capucine Baldini, Josep Tabernero, Aaron Hansen, Adnan Nagrial, Kate Roberts, Rohit Joshi, Elizabeth Ahern, Douglas Orr, Najeeb Al Hallak, Brian A. Van Tine, David Waller, Salah Nabhan, Allison Drew, Marc Ballas. Orally administered MOMA-341 as monotherapy or combination therapy in participants with advanced or metastatic solid tumors: Phase 1 study design [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B003.
Nature · 2024
Stephane Ferretti、Jacques Hamon、Ruben de Kanter 等
The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1-6. Despite advances in treatment with immune checkpoint inhibitors7-10, there is an unmet need in the treatment of MSI cancers11-14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.
ACS medicinal chemistry letters · 2025
Robert B Kargbo
Recent efforts have identified WRN helicase as a critical dependency in mismatch repair-deficient (dMMR) cancers. Small molecules targeting WRN demonstrate selective activity in microsatellite instability-high (MSI-H) models. These compounds impair tumor growth and promote cancer cell death by disrupting genome maintenance pathways, highlighting a promising therapeutic strategy for genetically defined, treatment-resistant tumors.
Annals of Oncology · 2025
M. Foote、J. Li、D. S. Tan 等
暂无摘要
eLife · 2019
Simone Lieb、Silvia Blaha-Ostermann、Elisabeth Kamper 等
Targeted cancer therapy is based on exploiting selective dependencies of tumor cells. By leveraging recent functional screening data of cancer cell lines we identify Werner syndrome helicase (WRN) as a novel specific vulnerability of microsatellite instability-high (MSI-H) cancer cells. MSI, caused by defective mismatch repair (MMR), occurs frequently in colorectal, endometrial and gastric cancers. We demonstrate that WRN inactivation selectively impairs the viability of MSI-H but not microsatellite stable (MSS) colorectal and endometrial cancer cell lines. In MSI-H cells, WRN loss results in severe genome integrity defects. ATP-binding deficient variants of WRN fail to rescue the viability phenotype of WRN-depleted MSI-H cancer cells. Reconstitution and depletion studies indicate that WRN dependence is not attributable to acute loss of MMR gene function but might arise during sustained MMR-deficiency. Our study suggests that pharmacological inhibition of WRN helicase function represents an opportunity to develop a novel targeted therapy for MSI-H cancers.
Cancer Research · 2025
J. Taygerly、Michael P. DeMartino、Brian T. Jones 等
Recent large-scale genome wide CRISPR screens identified Werner (WRN) Helicase as uniquely essential to cell survival specifically in the microsatellite instability-high (MSI-H) cancer setting. This synthetic lethal relationship elevated WRN as an attractive precision therapeutic target for the treatment of MSI-H cancers, irrespective of tumor type. High-throughput screening identified a hit characterized by low potency inhibition of ATPase function. This poster describes the systematic optimization of this hit resulting in the discovery of clinical candidate GSK4418959, a novel, potent and selective small molecule that binds to WRN in an allosteric pocket and inhibits ATPase and DNA unwinding functions in an ATP-competitive manner. GSK4418959 phenocopies the genetic silencing studies in cells and organoids and accordingly, elicits complete tumor regression in murine xenograft MSI-H models (CDX and PDX) following oral dosing. Importantly, no response is observed in analogous microsatellite stable (MSS) models, exemplifying the precision effect of the WRN inhibition mechanism. GSK4418959 will be investigated as a potential treatment for patients with MSI-H cancer, including those who have been treated with and failed at least one line of checkpoint immunotherapy for their advanced disease.
Joshua P. Taygerly, Michael P. DeMartino, Brian T. Jones, Edward J. Brnardic, Joshua E. Cottom, Yang Lee, Diana M. Munoz, Claire Neilan, Sunjay Sethi, Robert A. Reid, Apirat Chaikuad, Lisa M. Shewchuk, Ethan McSpadden, Daniel L. Severance, Kira Campbell, Philip Landis, Jay P. Jain, Richard Zhang, Leng Nickels, Dennis K. Murphy, Hans C. Eberl, Muzaffar Alam, Melissa Fleury, Lara K. Leister, Tessa Lynch-Colameta, James P. Phelan, Michael D. VanHeyst, Amberly B. Sanford, Ann M. Rowley, Hongyi Yu, Anna Rutkowska-Klute, Thilo Werner, Stephan Gade, Damian Hruszkewycz, Tyler Higgins, Xin Linghu, Ian S. Young, An D. Nguyen, Sabrina Bedard, Eldridge N. Nartey, Nanhua Deng, Yang Peng, Jessica L. Schneck, Geeta Sharma, Yanhua Rao, Paul A. Barsanti, Michael A. White, Benjamin Schwartz. Discovery of GSK4418959 (IDE275): A novel, non-covalent, reversible Werner Helicase inhibitor and a new potential therapeutic for the treatment of MSI-H cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5750.
为什么值得关注
编辑短评WRN共价抑制剂RO7589831（VVD-133214）的首次人体1期试验第1部分，评估了患者中的递增剂量。