Targeted cancer ablation via programmable sensing of amplified oncogenic RNA

Authors

Zhang, M., Hu, Y., Yamada-Hunter, S. A., Sotillo, E., Dai, H., Call, C. C., Tousley, A. M., Kim, S. J., Liu, W., Winslow, M. M., Mackall, C., Gao, X. J.

Abstract

Selectively eliminating cancer cells based on their oncogenic drivers holds great promise but remains challenging for targeted cancer therapy. Here, we present ORCA (Oncogenic RNA-triggered Cancer Ablation), a programmable and modular platform that couples RADAR-based detection of oncogenic RNA with conditional expression of therapeutic payloads in cancer cells. We identify RADAR sensors targeting the transcripts of endogenously amplified oncogenes, including MYC, FGFR2 and wild-type KRAS in colorectal and gastric cancer cells. Focusing on colorectal cancer (CRC) driven by extrachromosomal DNA-amplified MYC, we demonstrate targeted ablation of high-MYC cancer cells using two orthogonal strategies: anti-CD19 CAR-T therapy and enzyme-prodrug therapy. In vivo delivery of ORCA using adeno-associated virus (AAV) suppresses tumor growth in a subcutaneous xenograft model and prolongs survival in a CRC liver metastasis model. ORCA establishes oncogenic RNAs as actionable inputs for targeted cancer therapy via programmable RNA sensing, thus offering a strategy to target tumors through the transcripts of otherwise difficult-to-drug oncogenes such as MYC.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Nov 2026.

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