Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer-related deaths in the United States [1]. Recent years have seen a steady increase in CRC incidences among adults under the age of 55 [1]. CRC originates from the normal colonic epithelium through the progressive accumulation of genetic and epigenetic alterations in oncogenes and tumor suppressor genes [2]. CRC patients are typically treated with 5-fluorouracil (5-FU)-based chemotherapy in combination with targeted drugs such the anti-VEGF antibody bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab in the first line depending on presence of RAS mutations [3]. While most advanced and metastatic CRCs initially respond to therapeutic treatment, they often progress after initial treatment and become refractory to chemotherapy and targeted therapies [4]. Treatment failure and recurrence are major causes of mortality in CRC patients [5]. Developing new and more efficacious anticancer agents is crucial for improving CRC treatment.

CRC is a heterogenous disease with several major molecular subtypes [6]. About 15 % of CRCs exhibit a form of genomic instability known as microsatellite instability (MSI), characterized by increased mutation rates in short-tandem microsatellite repeat sequences [7]. MSI drives colorectal tumor initiation and progression and is caused by deficiency in DNA mismatch repair (MMR) due to genetic and epigenetic silencing of MMR proteins [8], [9], [10]. Compared to microsatellite stable (MSS) CRCs, MSI CRCs are typically less responsive to chemotherapy [11], but often have high levels of tumor-infiltrating lymphocytes (TILs) and sustained responses to immune checkpoint inhibitor (ICI) therapy [12], [13]. However, a significant portion of MSI CRCs do not respond to ICIs or ultimately develop resistance [11]. There is an unmet need for new therapies against therapy-refractory MSI CRC.

Synthetic lethality is a powerful strategy for targeting oncogenic drivers [14], [15]. Recent studies have shown that MSI cancer cells rely on Werner (WRN), a member of RecQ family DNA helicases, for survival [16], [17], [18], [19]. Inhibiting WRN has emerged as a promising therapeutic approach to target MSI cancers. Several highly potent small-molecule WRN inhibitors have been discovered, exhibiting striking in vitro and in vivo activities against MSI cancers [20], [21], [22]. Two of these WRN inhibitors, including HRO761 and VVD-133214, have recently entered clinical trials [23]. Here, 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.