1. Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.
- Author
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Bowling EA, Wang JH, Gong F, Wu W, Neill NJ, Kim IS, Tyagi S, Orellana M, Kurley SJ, Dominguez-Vidaña R, Chung HC, Hsu TY, Dubrulle J, Saltzman AB, Li H, Meena JK, Canlas GM, Chamakuri S, Singh S, Simon LM, Olson CM, Dobrolecki LE, Lewis MT, Zhang B, Golding I, Rosen JM, Young DW, Malovannaya A, Stossi F, Miles G, Ellis MJ, Yu L, Buonamici S, Lin CY, Karlin KL, Zhang XH, and Westbrook TF
- Subjects
- Adaptive Immunity drug effects, Animals, Apoptosis drug effects, Cell Line, Tumor, Cytoplasm drug effects, Cytoplasm metabolism, Female, Gene Amplification drug effects, Humans, Introns genetics, Mice, Molecular Targeted Therapy, Proto-Oncogene Proteins c-myc metabolism, RNA Splicing drug effects, RNA Splicing genetics, RNA, Double-Stranded metabolism, Signal Transduction drug effects, Spliceosomes drug effects, Triple Negative Breast Neoplasms genetics, Antiviral Agents pharmacology, Immunity drug effects, Spliceosomes metabolism, Triple Negative Breast Neoplasms immunology, Triple Negative Breast Neoplasms pathology
- Abstract
Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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