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.

本研究对经WRN解旋酶抑制剂HRO761处理的SW48异种移植模型来源的肿瘤样本实施全外显子组测序（Whole Exome Sequencing, WES），以探究获得性耐药的潜在机制。获得性耐药是肿瘤学领域靶向治疗维持持续疗效的重大挑战，而错配修复缺陷（dMMR）肿瘤的耐药问题尤为显著——这类肿瘤以更高突变负荷为特征，因而具备更强的适应度景观探索能力。初始HRO761治疗后肿瘤快速复发，且再次给药时无应答，提示该模型体系中已产生耐药性。本研究通过全外显子组测序对该耐药机制进行表征，旨在明确体内环境下WRN解旋酶区域内赋予HRO761耐药性的特异性遗传变异。因此，本数据集为WRN抑制剂获得性耐药的遗传基础提供了关键见解，可为开发针对微卫星不稳定（Microsatellite Instability, MSI）癌症的更持久治疗策略提供参考依据。