Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
Josep Carreras Leukemia Research Institute and Department of Biomedicine, School of Medicine, University of Barcelona, 08036, Barcelona, Spain.
Nat Commun. 2020 Oct 8;11(1):5060. doi: 10.1038/s41467-020-18875-x.
Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.
融合致癌基因（FOs）在许多癌症类型中很常见，是肿瘤发展的强大驱动因素。由于它们的表达仅限于癌细胞，并且其消除会诱导 FO 驱动的癌症中的细胞凋亡，因此 FOs 是有吸引力的治疗靶标。然而，专门针对由此产生的嵌合产物具有挑战性。基于 CRISPR/Cas9 技术，在这里，我们通过针对涉及重排的两个内含子设计了一种简单、高效且非患者特异性的基因编辑策略，从而能够在癌细胞中特异性地强力破坏 FO。作为其潜在功效的概念验证，我们证明了基于内含子的转录因子或酪氨酸激酶 FOs 靶向在减少体内模型中的肿瘤负担/死亡率方面的功效。这里提出的 FO 靶向方法可能为选择性消除癌细胞开辟新的视野。
