Abstract 1377: Identification and validation of WRN as a novel synthetic lethality target in context of microsatellite instability

Abstract

Abstract Despite the significant clinical success of the Immuno-Oncology treatment of microsatellite instability (MSI) patients, there remains huge unmet medical need because of mechanisms of resistance. Through an effort to analyze publicly available large-scale shRNA screening and CRISPR screening, we surprisingly found that WRN is a potent synthetic lethality target in the context of MSI. WRN is an enzyme known as the “Werner syndrome ATP-dependent helicase”. WRN is involved in multiple cellular functions, including DNA repair and telomere maintenance. Silencing of WRN by RNAi and CRISPRi in a panel of MSI-H cells lead to tumor cell growth inhibition in vitro and in vivo, thus demonstrated WRN is a novel synthetic lethality target in context of MSI. Our discovery has recently been cross-validated by multiple independent studies1-4. Furthermore, we also report here the first time that silencing of WRN by RNAi and CRISPRi in DLD1, a MSI-H cell, does not lead to tumor cell inhibition. Taken together, our data using independent genetic approach CRISPRi in vitro and in vivo, further highlight fundamental importance of WRN as a synthetic lethality target in some, but not all, MSI context.