Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

Bowling, Elizabeth A.; Wang, Jarey; Gong, Fade; Wu, Wenyi; Neill, Nicholas J.; Kim, Ik Sun; Tyagi, Siddhartha; Orellana, Mayra; Kurley, Sarah J.; Dominguez-Vidaña, Rocio; Chung, Hsiang-Ching; Hsu, Tiffany; Dubrulle, Julien; Saltzman, Alexander B.; Li, Heyuan; Meena, Jitendra K.; Canlas, Gino M.; Chamakuri, Srinivas; Singh, Swarnima; Simon, Lukas M.; Olson, Calla; Dobrolecki, Lacey E.; Lewis, Michael T.; Zhang, Bing; Golding, Ido; Rosen, Jeffrey M.; Young, Damian W.; Malovannaya, Anna; Stossi, Fabio; Miles, George; Ellis, Matthew J.; Yu, Lihua; Buonamici, Silvia; Lin, Charles Y.; Karlin, Kristen L.; Zhang, Xiang H.-F.; Westbrook, Thomas F.

doi:10.1016/j.cell.2020.12.031

Cited by 113 publications

(92 citation statements)

References 141 publications

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“…While PRMT enzymes are often classified as epigenetic targets based on their histone substrates, PRMTs have a much broader set of targets, especially RNA-binding proteins involved in mRNA splicing 39,40 . Given these broad roles of type I PRMT on RNA splicing, our discovery is consistent with the recent report showing that spliceosome-targeted therapies result in intron-containing transcripts that form double-stranded RNAs 38 .…”

Section: Discussionsupporting

confidence: 90%

“…It was recently reported that disruption of mRNA splicing through inhibition of splicing regulatory kinases could trigger an antiviral response through the induction of misspliced RNAs. In particular, mis-spliced mRNAs with retained introns formed double-stranded structures that accumulated in the cytoplasm 38 . Given the broad effects of type I PRMT on mRNA splicing 13,16,39,40 , we hypothesized that induction of dsRNA formation in response to MS023 treatment was due to direct deregulation of RNA splicing 41,42 .…”

Section: Type I Prmt Inhibition Induces Dsrna Accumulation From Intron-retained Rnasmentioning

confidence: 99%

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Altered RNA splicing initiates the viral mimicry response from inverted SINEs following type I PRMT inhibition in Triple-Negative Breast Cancer

Arrowsmith

Nie

et al. 2021

Preprint

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Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here, we undertook a screen of epigenetic chemical probes to systematically uncover the epigenetic regulators critical for TNBC growth. We identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), as having anti-tumor growth activity in TNBC in vitro and in vivo. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses pre- and post-MS023 treatment is a functional biomarker and determinant of response; and these observations extend to a panel of patient-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA (dsRNA). The observed dsRNA accumulation is derived, at least in part, from inverted-repeat Alus (IR-Alus), many of which are expressed from retained introns induced by MS023, which inhibits arginine methylation of RNA-binding proteins and alters mRNA splicing machinery. Together, our results represent a shift in understanding the anti-tumor mechanism of type I PRMT inhibitors and provide a novel rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

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Section: Discussionsupporting

confidence: 90%

Section: Type I Prmt Inhibition Induces Dsrna Accumulation From Intron-retained Rnasmentioning

confidence: 99%

Altered RNA splicing initiates the viral mimicry response from inverted SINEs following type I PRMT inhibition in Triple-Negative Breast Cancer

Arrowsmith

Nie

et al. 2021

Preprint

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“…In this study we chose to interfere with abnormal transcriptome in resistant cancer cells with ribonucleoside analogs, although there are other possible ways for targeting transcriptome. A good example would be spliceosome-targeted small molecule inhibitors that interfere with RNA splicing, leading to accumulation of double-stranded RNA, which triggers antiviral immune response in TNBC cells [21]. What remains to be determined is which transcriptome-targeted therapies would provide maximum efficacy against resistant cancer cells, while sparing normal cells in the body.…”

Section: Basis Of Rna-targeting Strategy In Resistant Cancer Cellsmentioning

confidence: 99%

Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine

2021

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Highly adaptable breast cancer cells that can opportunistically switch between proliferation and quiescence are often responsible for disease relapse. We have developed a function-based selection strategy for such resistant cells, exemplified by SUM149-MA and FC-IBC02-MA triple-negative breast cancer cells. We have also reported that a lengthy treatment with low-dose 6-mercaptopurine, a clinically useful anti-inflammatory drug, inhibits such resistant cells. To more rigorously test the clinical suitability of 6-mercaptopurine, here we investigated effects of further lowering its dose and the possibility of overcoming resistance to single-drug treatment by combining the drug with another ribonucleoside analog 5-azacitidine.We found that that a lengthy treatment with 1 µM 5-azacitidine, without a significant effect on cell proliferation, sensitized cancer cells to the inhibitory effects of lowdose 6-mercaptopurine. Importantly, treatment for several weeks with low doses of 6-mercaptopurine and/or 5-azacitidine did not render cancer cells resistant to chemotherapeutic drugs doxorubicin or paclitaxel. In fact, the cells became more sensitive to chemotherapeutic drugs upon treatment with 6-mercaptopurine and/ or 5-azacitidine. Our analyses of protein markers of epithelial-to-mesenchymal transition indicated that treatments with 6-mercaptopurine and/or 5-azacitidine do not significantly reverse this process in our model. Our results showed that safe drugs such as low-dose 6-mercaptopurine singly or combined with 5-azacitidine, which are suitable for use prior to disease relapse, have a potential of inhibiting highly resistant triple-negative breast cancer cells.

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“…Furthermore, it is unknown why human tumor cells are more sensitive to these siRNA induced death than human normal cells. It was reported that many oncogenic insults deregulated RNA splicing leading to hypersensitivity of tumors to spliceosome targeted therapies (STTs) which caused widespread cytoplasmic accumulation of dsRNA to trigger antiviral signaling and extrinsic apoptosis ( 33 ), suggesting that the sensitivity of tumor cells might be due to the abnormally activated oncogenic gene. The detailed molecules and signaling pathways need to be further studied.…”

Section: Discussionmentioning

confidence: 99%

siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis

et al. 2021

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Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells in vivo. 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.

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Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

Cited by 113 publications

References 141 publications

Altered RNA splicing initiates the viral mimicry response from inverted SINEs following type I PRMT inhibition in Triple-Negative Breast Cancer

Altered RNA splicing initiates the viral mimicry response from inverted SINEs following type I PRMT inhibition in Triple-Negative Breast Cancer

Inhibition of resistant triple-negative breast cancer cells with low-dose 6-mercaptopurine and 5-azacitidine

siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis

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