Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Colorectal cancer (CRC) remains a leading cause of cancer mortality in the US.
• Microsatellite instability (MSI), resulting from DNA mismatch repair deficiency, drives CRC development and often confers resistance to immunotherapy.
• MSI cancer cells exhibit a dependency on the Werner (WRN) helicase for survival.

Purpose of the Study:

• To review the role of WRN as a synthetic lethal target in MSI CRC.
• To summarize the development of WRN inhibitors as a novel therapeutic class for MSI CRC.
• To highlight emerging treatments for immunotherapy-resistant MSI CRC.

Main Methods:

• Review of recent scientific literature on WRN function in MSI CRC.
• Analysis of studies investigating WRN inhibitors in preclinical and clinical settings.
• Summary of the development pipeline for WRN-targeted therapies.

Main Results:

• WRN is essential for the survival of MSI cancer cells.
• Small-molecule WRN inhibitors demonstrate potent anti-cancer activity in vitro and in vivo.
• Two WRN inhibitors, HRO761 and VVD-133214, have advanced to clinical trials.

Conclusions:

• Targeting WRN represents a promising synthetic lethal strategy for MSI CRC.
• WRN inhibitors offer a new therapeutic avenue for patients with immunotherapy-resistant MSI CRC.
• Further clinical investigation of WRN inhibitors is warranted.