Patient-derived xenografts (PDXs) are high-fidelity in vivo tumor models that accurately reflect many key aspects of human cancer. In contrast to cancer cell lines or genetically engineered mouse models, the utility of PDXs has been limited by the inability to perform targeted genome editing of these tumors. To address this limitation, we have developed methods for CRISPR-Cas9 editing of PDXs using a tightly regulated, inducible Cas9 vector that does not require in vitro culture for selection of transduced cells. We demonstrate the utility of this platform in PDXs to analyze genetic dependencies by targeted gene disruption and to analyze mechanisms of acquired drug resistance by site-specific gene editing, using templated homology-directed repair. This flexible system has broad application to other explant models and substantially augments the utility of PDXs as genetically programmable models of human cancer.

源自患者的异种移植物 (PDX) 是高保真体内肿瘤模型，可准确反映人类癌症的许多关键方面。与癌细胞系或基因工程小鼠模型相比，PDX 的效用受到无法对这些肿瘤进行靶向基因组编辑的限制。为了解决这一限制，我们开发了使用严格调节的可诱导 Cas9 载体对 PDX 进行 CRISPR-Cas9 编辑的方法，该载体不需要体外培养来选择转导细胞。我们展示了该平台在 PDX 中的实用性，可通过靶向基因破坏分析遗传依赖性，并使用模板化同源定向修复通过位点特异性基因编辑分析获得性耐药机制。