Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
Nat Genet. 2021 Apr;53(4):529-538. doi: 10.1038/s41588-021-00819-w. Epub 2021 Mar 22.
Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.
从高突变负荷的成人癌症的 CRISPR 为基础的筛选中，涌现出令人兴奋的治疗靶点。然而，一个关键问题是，功能基因组方法是否会在儿科癌症中产生新的靶点，儿科癌症的突变通常很少，这些突变往往编码被认为是具有挑战性的药物靶点的蛋白质。为了解决这个问题，我们创建了第一代儿科癌症依赖图谱，代表 13 种儿科实体瘤和脑肿瘤类型。对 82 种儿科癌细胞系进行了全基因组 CRISPR-Cas9 功能丧失筛选，以鉴定细胞存活所需的基因。与儿科癌症携带较少体细胞突变的发现相反，我们发现儿科癌细胞系的遗传依赖性与成人模型相似。儿科癌症依赖图谱的研究结果为正在进行的精准医学临床试验提供了临床前支持。在儿科癌症中观察到的脆弱性往往与成人癌症中的不同，这表明重新利用成人肿瘤药物不足以解决儿童癌症。
