WRN Inhibitors May Address Immunotherapy Resistance in MSI+ Tumors

Inhibition of WRN helicase may present an option for patients with resistance to immunotherapies whose tumors express MSI.

RO7589831, a WRN inhibitor, was met with positive results in a dose-escalation trial in patients with microsatellite instability (MSI)-expressing tumors, according to data presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting.¹

Promising New Approach for Patients with MSI Cancers Resistant to Immunotherapy

At the AACR meeting in April, Timothy A. Yap, MBBS, PhD, FRCP, cited data showing that 40% to 70% of patients with MSI-expressing cancers either do not respond to immunotherapy or eventually develop resistance and highlighted the significant need demonstrated by this information for alternative treatment strategies. WRN helicase, an enzyme critical for DNA repair, has emerged as a promising therapeutic target in MSI-expressing tumors. RO7589831, a first-in-class WRN inhibitor, has shown the ability to induce DNA damage and suppress tumor growth in preclinical models of MSI-expressing cancers.

In a first-in-human, open-label, dose-escalation study (NCT06004245), researchers evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and early signs of efficacy of RO7589831 in 44 patients with advanced MSI and/or deficient MMR solid tumors. These included both colorectal (CRC; n = 22) and non-CRC (n = 22) cancers. Most patients (89%) had received prior ICI therapy, and patients had a median of 3 prior lines of treatment (range, 1-12).

RO7589831 was administered orally once or twice daily, with doses ranging from 150 mg to 2000 mg. The drug was rapidly absorbed, with a median time to peak concentration of about 2.6 hours and a short half-life of 4.4 hours. No dose-limiting toxicities were reported, and the maximum tolerated dose (MTD) had not been reached as of the data cutoff.

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

The most common adverse effects (AEs) were gastrointestinal in nature: nausea (52.3%), diarrhea (34.1%), and vomiting (31.8%). Grade 3 treatment-related AEs (TRAEs) occurred in some patients, with 2 having nausea (4.3%), 2 having increased liver enzymes (4.3%), 1 patient having fatigue (2.1%), and 1 patient having anemia (2.1%). No grade 4 or more severe toxicities were observed.

Among 32 evaluable MSI-expressing patients, 4 had partial responses by RECIST v1.1 criteria (2 confirmed and 2 ongoing unconfirmed), and 20 (62.5%) had stable disease. Of those with partial responses, 2 had endometrial cancer, 1 had ovarian cancer, and 1 had CRC. The overall disease control rate was 68.8% (95% CI, 51.13%-86.37%). All patients whose disease responded to treatment on imaging also showed significant metabolic responses on FDG-PET scans, and circulating tumor DNA (ctDNA) responses were observed in those 8 of 9 patients with stable disease and both patients displaying confirmed partial responses.

These early findings provide the first clinical proof-of-concept that WRN inhibition may be an effective strategy in treating MSI-expressing cancers, including in patients who have failed or progressed on immunotherapy. Further dose optimization is underway to establish the recommended Phase 2 dose (RP2D).

Nursing Considerations

Oncology nurses are likely familiar with the term microsatellite instability (MSI), though it can sometimes be challenging to understand or explain to patients and families. In simple terms, MSI is a change that occurs when a cell’s natural ability to fix DNA mistakes stops working properly. Normally, cells use a system called mismatch repair (MMR) to correct small errors that happen when DNA is copied. When this system is not functioning, these errors accumulate, especially in areas of DNA called microsatellites. When many of these errors are present, the tumor is referred to as “MSI-high.” This is most commonly seen in colorectal, endometrial, and gastric cancers. MSI-high tumors often respond better to immunotherapy, such as immune checkpoint inhibitors (ICI) like pembrolizumab or nivolumab. However, not all patients benefit from these treatments, and some eventually stop responding. This highlights the need for alternative targeted therapies, and researchers are actively exploring new treatment options for these patients.²

Oncology nurses caring for patients receiving WRN inhibitors like RO7589831 should be prepared to educate patients about this new approach. Since RO7589831 is an oral agent, nurses play a key role in reinforcing adherence, reviewing dosing schedules, and addressing potential barriers. Common side effects, such as nausea, vomiting, and diarrhea, should be managed proactively with supportive medications to allow patients to tolerate therapy as much as possible.

Oncology nurses can also encourage clinical trial participation in patients with MSI-expressing cancers who may be eligible for treatment with WRN inhibitors, helping them explore cutting-edge treatment options.

References

1. Yap TA, Smith J, Lee A, et al. First-in-human study of RO7589831, a WRN helicase inhibitor, in patients with microsatellite instability (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors. Presented at: American Association for Cancer Research Annual Meeting; April 27, 2025; Chicago, IL. Abstract 10419.
2. Nádorvári ML, Lotz G, Kulka J, Kiss A, Tímár J. Microsatellite instability and mismatch repair protein deficiency: equal predictive markers?. Pathol Oncol Res. 2024;30:1611719. Published 2024 Apr 9. doi:10.3389/pore.2024.1611719