Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells

In the current field of tumor treatment, precision medicine continues to be a research hotspot and development trend. With the advancement of science and technology, we have begun to more accurately understand the characteristics of tumor cells and their dependencies for survival, in hopes of finding new therapeutic targets. Particularly, strategies based on the principle of synthetic lethality, which involves the development of drugs for targeted therapy against specific genetic defects in tumors, have become a new hope for solving challenging issues in cancer treatment. The synthetic lethality strategy is primarily based on the molecular-level differences between tumor cells and normal cells. By targeting molecular mechanisms essential for tumor cell survival but less critical for normal cells, the goal is to achieve selective killing of tumor cells without harming normal cells.

Microsatellite Instability (MSI) is a tumor genetic characteristic commonly seen in some mismatch repair (MMR)-deficient cancers, such as colorectal cancer, endometrial cancer, and gastric cancer. Due to the instability present at the genomic DNA level in these types of tumor cells, they exhibit numerous new antigens on their surfaces, thereby showing certain sensitivity to immunotherapy. However, these tumors also exhibit resistance to immunotherapy, especially in metastatic cases, making the development of new therapeutic strategies extremely urgent.

The WRN protein is an enzyme with helicase and exonuclease activity, playing an important role in maintaining genomic integrity. Genetic loss of WRN leads to Werner syndrome, characterized by premature aging and an increased risk of cancer. Recent studies have shown a synthetic lethality relationship between WRN loss and MSI-type tumors. MSI tumor cells, to resolve replication stress due to extended TA dinucleotide repeats, rely on the unwinding function of the WRN protein. This phenomenon makes WRN a potential therapeutic target for MSI tumors.

In this study, the research team used CRISPR-Cas9 gene-editing technology to perform precise functional mapping of the WRN protein, confirming the dependency of MSI-type cells on WRN helicase activity. They screened a series of small molecular compounds potentially inhibiting WRN and ultimately developed highly efficient and selective covalent inhibitors of WRN helicase. These compounds specifically inhibited the growth of MSI cell models both in vitro and in vivo, by simulating WRN loss and inducing DNA double-strand breaks and DNA damage. The study found that the compound’s activity was related to TA repeat expansions and alterations in the MMR pathway, confirming its high efficacy in organotypic samples resistant to immunotherapy and in patient-derived xenograft (PDX) models.

This research was jointly completed by the Wellcome Sanger Institute in Cambridge, UK; institutions in Pennsylvania and Massachusetts, USA; Stevenage, UK; Heidelberg, Germany; the Babraham Institute in Cambridge, UK; the Italian Cancer Research Institute in Candiolo; Ideaya Biosciences in South San Francisco, California, USA; and the Netherlands Cancer Institute. The research team was led by Dr. Gabriele Picco, with Dr. Mathew J. Garnett as the corresponding author. The research findings were published in the journal “Cancer Discovery” in 2024.

Summarizing the core value of this study, it scientifically provides strong evidence for WRN as a new therapeutic target for MSI-type cancers. From a clinical application perspective, it developed a series of highly efficient and selective WRN helicase inhibitors, offering a potential new solution for the precision treatment of MSI tumors. Especially for those MSI-type tumor patients resistant to existing immunotherapy methods, these new WRN helicase inhibitors may offer dramatic therapeutic breakthroughs.

Moreover, the study mentions TA repeat expansion levels and MMR pathway alterations as biomarkers of compound activity, having significant implications for potentially identifying patient groups most likely to benefit from WRN inhibitor treatment. These findings not only provide crucial clues for future precision medicine in MSI-type cancers but also offer important tools and new perspectives for understanding WRN biology.

This study holds profound significance for both the scientific community and clinical applications. It not only provides new directions for MSI-type tumor treatment strategies but also offers strong evidence for the further application of the synthetic lethality concept in cancer therapy. As these compounds undergo further evaluation and potential clinical trials, we move closer to offering hope to those patients urgently in need of new treatment options.