HRO761

In this study, we characterized resistance mechanisms using the clinical candidate HRO761 and two novel inhibitors in MSI cell lines and xenograft models...This chemotype-specific resistance profile suggests opportunities for developing next-generation inhibitors that retain activity against resistant variants and for implementing rational treatment strategies with existing inhibitors. Overall, our findings demonstrate that on-target resistance to WRN inhibitors emerges rapidly in dMMR backgrounds but also highlight potential approaches to overcome resistance, supporting continued development of WRN-targeted therapies for MSI cancers.

P1, N=327, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: May 2029 --> Aug 2027 | Trial primary completion date: May 2029 --> Aug 2027

Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, 'off-DNA' states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation 'on-DNA' inhibitors to overcome resistance.

Notably, 35% of patients in the dostarlimab arm of the RUBY trial received subsequent immunotherapy off-protocol, highlighting the gap between evolving clinical behavior and available evidence...Additional reports indicate that combining immune checkpoint inhibitors with anti-vascular endothelial growth factors or multi-kinase inhibitors, such as lenvatinib or cabozantinib, may enhance immune reactivation even in microsatellite-stable or carcinosarcoma histologies...In contrast, synthetic lethality strategies, such as the Werner helicase inhibitor HRO761 in high microsatellite instability tumors, represent promising non-immune-based rechallenge approaches. As immune checkpoint inhibitor exposure becomes commonplace in earlier treatment settings, there is an urgent need for biologically informed, individualized strategies to guide post-immune checkpoint inhibitor management. Future progress will depend on refining rechallenge criteria, optimizing combination regimens, and developing predictive biomarkers to identify patients most likely to benefit from retreatment.

Two of these WRN inhibitors, HRO761 and VVD-133214, have recently entered clinical trials. In this review, we summarize recent studies on WRN as a synthetic lethal target in MSI CRC and the development of WRN inhibitors as a new class of anticancer agents.

In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.

P1, N=327, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2030 --> May 2029 | Trial primary completion date: Jan 2030 --> May 2029

Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.

The triazolo-pyrimidine compound HRO761 is the first WRN inhibitor to enter clinical trials, but research on this scaffold remains limited...S35 demonstrated favorable oral pharmacokinetic properties, with oral administration resulting in dose-dependent tumor growth inhibition in the SW48 xenograft model. These findings provide a promising outlook for the development of WRN inhibitors for the treatment of MSI tumors.

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.

P1, N=327, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2026 --> Jan 2030 | Trial primary completion date: Aug 2026 --> Jan 2030

Key eligibility criteria include: 1) Patients with advanced unresectable or metastatic MSIhi or dMMR solid tumors who have progressed after or are intolerant to prior standard therapy; 2) patients should have received at least one prior line of chemotherapy or targeted therapy, and prior immune checkpoint inhibitor therapy (Arm A and C). Checkpoint inhibitor therapy is permitted but not required and prior adjuvant therapy is allowed in Arm B.