Exome sequencing of HRO761 treated SW48 xenografts
Whole exome sequencing (WES) was performed on tumor samples derived from SW48 xenograft models treated with the WRN helicase inhibitor HRO761 to investigate mechanisms of acquired resistance. Acquired resistance poses a significant challenge to the sustained efficacy of targeted therapies in oncology, and this may be particularly pronounced in mismatch repair deficient (dMMR) tumors, which are characterized by a higher mutational burden and thus an increased capacity to explore fitness landscapes. The rapid emergence of tumor regrowth after initial HRO761 treatment and subsequent lack of response upon rechallenge suggested the development of resistance in these models. By characterizing these resistance mechanisms using WES, we aimed to identify specific genetic alterations within the WRN helicase region that confer resistance to HRO761 in an in vivo setting. This dataset therefore provides crucial insights into the genetic underpinnings of acquired resistance to WRN inhibitors, informing strategies for developing more durable therapeutic approaches for MSI cancers.