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oai:docta.ucm.es:20.500.14352/1339542026-03-13T00:49:35Zcom_20.500.14352_14col_20.500.14352_15

00925njm 22002777a 4500 dc Nieto Sanchez, A. author Roda Navarro, Pedro author Rodríguez Perales, Sandra author 2025-12-25 Oncogene amplifications fuel some of the most lethal, therapy‑refractory cancers, yet remain clinically untargeted. We report a single‑guide CRISPR/Cas9 strategy that converts the sheer copy‑number excess of oncogene amplicons into an Achilles' heel. A solitary intronic double‑strand break is innocuous in diploid genomes but collapses oncogene amplification‑positive cells across neuroblastoma, small‑cell lung and colorectal carcinoma models, driving > 90% loss of viability, G₂/M blockade and catastrophic DNA‑damage signalling. Amplified‑locus cleavage rewires transcription toward cell death activation, necroptosis and cGAS-STING-mediated immunogenic cell death, enabling dendritic‑cell cross‑priming and T‑cell activation and proliferation. In xenografts, delivery of the intronic sgRNA shrinks tumours by 90%, prolongs survival and remodels the innate tumour microenvironment. Deep sequencing confirms negligible off‑target editing, and combination with doxorubicin achieves supra‑additive killing. These findings establish amplification density, not sequence content, as a tractable, tumour‑exclusive target and unveil a dual‑action platform that is simultaneously cytotoxic and immunostimulatory. Editing of tumor amplifications therefore offers a blueprint for translating copy‑number aberrations into precision genome‑editing therapies for treatment‑resistant cancers. Nieto-Sanchez A, Martinez-Lage M, Puig-Serra P, Carpintero S, Alonso-Yanez A, Ojeda-Walczuk P, Ibañez-Navarro M, Pita G, Moya FJ, Moreno C, Martin MC, Alonso R, Nuñez-Torres R, Sanchez-Arevalo Lobo VJ, Alonso-Guirado L, Malats N, Gonzalez-Neira A, Fernandez L, Roda-Navarro P, Torres-Ruiz R, Rodriguez-Perales S. Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling. Mol Cancer. 2025 Dec 22;25(1):21. doi: 10.1186/s12943-025-02542-0 1476-4598 10.1186/s12943-025-02542-0 https://hdl.handle.net/20.500.14352/133954 https://doi.org/10.1186/s12943-025-02542-0 41430241 https://link.springer.com/article/10.1186/s12943-025-02542-0 https://pubmed.ncbi.nlm.nih.gov/41430241/ Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling