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

M. Martinez-Lage, R. Torres-Ruiz (), P. Puig-Serra, P. Moreno-Gaona, M. C. Martin, F. J. Moya, O. Quintana-Bustamante, S. Garcia-Silva, A. M. Carcaboso, P. Petazzi, C. Bueno, J. Mora, H. Peinado, J. C. Segovia, P. Menendez and S. Rodriguez-Perales ()
Additional contact information
M. Martinez-Lage: Centro Nacional de Investigaciones Oncológicas (CNIO)
R. Torres-Ruiz: Centro Nacional de Investigaciones Oncológicas (CNIO)
P. Puig-Serra: Centro Nacional de Investigaciones Oncológicas (CNIO)
P. Moreno-Gaona: Centro Nacional de Investigaciones Oncológicas (CNIO)
M. C. Martin: Centro Nacional de Investigaciones Oncológicas (CNIO)
F. J. Moya: Centro Nacional de Investigaciones Oncológicas (CNIO)
O. Quintana-Bustamante: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER)
S. Garcia-Silva: Spanish National Cancer Research Centre
A. M. Carcaboso: Institut de Recerca Sant Joan de Deu
P. Petazzi: University of Barcelona
C. Bueno: University of Barcelona
J. Mora: Institut de Recerca Sant Joan de Deu
H. Peinado: Spanish National Cancer Research Centre
J. C. Segovia: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER)
P. Menendez: University of Barcelona
S. Rodriguez-Perales: Centro Nacional de Investigaciones Oncológicas (CNIO)

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18875-x

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