A New Breakthrough in Precision Treatment for MSI-H Tumors: Targeting WRN for Synthetic Lethality

On April 24, 2024, the prestigious journal Nature published two groundbreaking studies on WRN inhibitors, detailing Bayer’s Vividion Therapeutics’ VVD-133214 and Novartis’ HRO761. Both inhibitors are currently in Phase I clinical trials, highlighting a new frontier in the development of synthetic lethality-based therapies.

WRN: A Novel Synthetic Lethal Target in Cancer Treatment

WRN, a member of the RecQ helicase family, plays a key role in DNA replication, repair, transcription, and telomere maintenance, ensuring genomic stability and facilitating DNA damage repair. In microsatellite instability (MSI) tumor cells, WRN has emerged as a highly specific synthetic lethal target.

MSI refers to genomic instability caused by deficiencies in mismatch repair (MMR) systems, recognized as a critical driver of carcinogenesis. MSI has been identified in over 20 different tumor types, including colorectal, endometrial, and gastric cancers, with high prevalence in approximately 3% of tumors. Studies indicate that while MSI tumor patients often exhibit better immune responses and prognoses post-surgery, treatment outcomes for metastatic MSI-high (MSI-H) patients remain poor. These patients frequently face challenges such as chemotherapy resistance and low response rates to immunotherapy. Notably, WRN deficiency selectively induces cytotoxicity in MSI-H cancer cells while sparing microsatellite-stable (MSS) cells, underscoring its potential as a precision therapy target for MSI-H tumors.

Innovative Therapies: VVD-133214 and HRO761

VVD-133214, developed by Vividion Therapeutics, is a covalent allosteric inhibitor targeting WRN. This molecule specifically binds to the C727 residue of the WRN protein, exhibiting helicase inhibitory activity in the low nanomolar range. In MSI-H cells, VVD-133214 triggers extensive double-stranded DNA breaks, nuclear swelling, and cell death.

HRO761, developed by Novartis, is a non-covalent allosteric inhibitor that binds at the interface of the D1 and D2 helicase domains of WRN. This binding locks WRN in an inactive conformation and induces dose-dependent degradation of the WRN protein. In January 2024, HRO761 received implicit approval for clinical trials in China, with plans to treat advanced unresectable or metastatic MSI-H or mismatch repair-deficient (dMMR) solid tumors.

Prospects for WRN Inhibitor Development

Globally, over ten WRN-targeting drug candidates are currently in preclinical development. International efforts include Nerviano Medical Sciences’ EP2023070611W, Beactica Therapeutics’ WRN PROTAC, and Nimbus Therapeutics’ WRN inhibitor. Domestically, notable candidates include Insilico Medicine’s SM9432A and ISM2196, QinHao Pharma’s GH1581, Simcere Pharmaceutical’s ZM-3329, and Puhe Pharma’s PH027.

While progress in WRN inhibitor development has generally been slow, Bayer’s VVD-133214 and Novartis’ HRO761 have demonstrated significant promise by advancing quickly to Phase I clinical trials. These inhibitors showcase leading potential in precision treatment for MSI-H tumors. The emergence of WRN inhibitors marks a significant step forward in synthetic lethality-based cancer therapies, offering hope for groundbreaking treatment options for MSI-H tumor patients.

To support the development of WRN-targeted therapies, Kyinno has constructed HCT116-WRN-C727A-KI and HCT116-WRN-C727S-KI cell lines with site-specific editing. Validation data are available upon request—feel free to contact us for more information.

WRN Gene-Edited Cell Line List:

1. KC-4310 HCT116-WRN-C727A
2. KC-4311 HCT116-WRN-C727A
3. KC-4313 RKO-WRN-C727S
4. KC-4314 RKO-WRN-C727S
5. KC-4274 293T-WRN-C727A-KI
6. KC-4275 293T-WRN-C727S-KI
7. HCT116-WRN-C727S

In Vitro Drug Efficacy Validation of VVD-133214 and HRO761

DNA Sequencing Validation of In Situ Mutation

1. HCT116-WRN-C727A

2. RKO-WRN-C727S

3. HCT116-WRN-C727S

References:?

1. David A.Morales-Juarez,et al.,(2023).Clinical prospects of WRN inhibition as a treatment for MSI tumours.npj Precision Oncology,DOI:10.1038/s41698-022-00319-y.
2. Kristen A. Baltgalvis,et al.,(2024).Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.Nature,DOI:10.1038/s41586-024-07318-y.
3. Stephane Ferrett,et al.,(2024).Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.Nature,DOI:10.1038/s41586-024-07350-y.