Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-020-18875-x
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Funding
- Spanish National Research and Development Plan
- Instituto de Salud Carlos III
- FEDER [PI17/02303, DTS19/00111]
- AEI/MICIU EXPLORA Project [BIO2017-91272-EXP]
- CaixaImpulse [CI18-00017]
- Asociacion Espanola Contra el Cancer (AECC)
- European Research Council [CoG-2014-646903, PoC-2018-811220]
- Spanish Ministry of Science, Innovation and Universities [SAF2016, SAF2017-84248-P]
- Catalunya Government [SGR330, PERIS 2017]
- Spanish Cell Therapy cooperative research network (TERCEL) [RD16/0011/0011]
- AECC
- Beca FERO
- ISCIII/FEDER [PI17/01028]
- Obra Social La Caixa-Fundaci Josep Carreras
- ISCIII-FEDER [CP13/00189]
- Xarxa de Bancs de Tumors de Catalunya (XBTC - Pla Director d'Oncologia de Catalunya)
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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. Fusion oncogenes (FO) are common in cancers, but specific targeting of these chimeric genes are challenging. Here the authors report a CRISPR/Cas9 strategy that targets two intronic regions to disrupt the FOs in cancer cells and show that this approach reduces tumour growth and prolongs survival in animal models of cancer.
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