WRN is a DNA repair protein that has DNA unwinding and editing activities. Many tumors contain defects in components of the DNA repair machinery. In particular, loss of DNA mismatch repair enzymes results in a high mutational load and a DNA damage signature known as Microsatellite Instability (MSI). This condition creates an “Achilles’ heel” in which WRN becomes essential for tumor cell survival to repair mismatched DNA, specifically in MSI cancer. This condition is known as synthetic lethality, meaning that inactivation or inhibition of WRN specifically kills tumor cells with this Achilles’ heel.
Recent whole genome studies of cancer cell dependency revealed that WRN is one of the top-ranked targets showing synthetic lethality in a specific biomarker defined tumors (refs). Therefore, the Silicon Therapeutics team is developing a WRN antagonist as a precision therapeutic to target MSI tumors. The target patient population includes subsets of colorectal, gastric, ovarian cancer patients and others with the MSI biomarker signature. This predefined patient population provides an efficient development path to test our therapies with those most likely to benefit. We are planning to test our drug alone and in combination with other established therapies, including DNA damage targeting agents and immunotherapies.