In vivo CRISPR/Cas9 targeting of fusion oncogenes for selective elimination of cancer cells

Abstract

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. ; This work was supported by grants from the Spanish National Research and Development Plan, Instituto de Salud Carlos III, and FEDER (PI17/02303 and DTS19/00111 to S.R-P.); AEI/MICIU EXPLORA Project BIO2017-91272-EXP and CaixaImpulse (CI18-00017;FuGe) to S.R-P. RT-R. is supported by a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC). P.M. is supported by the European Research Council (CoG-2014-646903 and PoC-2018-811220), the Spanish Ministry of Science, Innovation and Universities (SAF2016), and the Catalunya Government (SGR330 and PERIS 2017). J.C.S. is supported by the Spanish Ministry of Science, Innovation and Universities (SAF2017-84248-P) and the Spanish Cell Therapy cooperative research network (TERCEL)(RD16/0011/0011). C.B. is supported by the AECC, Beca FERO, and the ISCIII/FEDER (PI17/01028). P.M. also acknowledges the financial support from the Obra Social La Caixa-Fundaci Josep Carreras. P.M. is an investigator of the Spanish Cell Therapy cooperative research network (TERCEL). A.M.C. acknowledges funding from ISCIII-FEDER (CP13/00189) and Xarxa de Bancs de Tumors de ...