Spliceosome-Targeted Therapies Induce dsRNA Responses

In a recent issue of Cell, Bowling et al. describe mechanism by which spliceosome-targeted therapies result in intron-containing transcripts that form double-stranded RNAs (dsRNAs), thereby activating tumor antiviral signaling (viral mimicry) and downstream adaptive immunity. RNA splicing mediated the spliceosome complex confers increased control gene expression. Aberrant can threaten cell fitness as exemplified synthetic lethal effects co-expressed mutations myelodysplastic syndrome (Goodall Wickramasinghe, 2020Goodall G.J. Wickramasinghe V.O. cancer.Nat. Rev. Cancer. 2020; 21 (Published online October 20, 2020): 22-36https://doi.org/10.1038/s41568-020-00306-0Crossref PubMed Scopus (125) Google Scholar). Since lethality is induced upon cumulative disruption components, small molecules referred to (STTs) have been developed target cancers harbor such hematological malignancies. Reduced has previously attributed aberrant disrupts cellular homeostasis. However, general mechanisms describing how STTs induce death remain poorly described. study al., 2021Bowling E.A. Wang J.H. Gong F. Wu W. Neill N.J. Kim I.S. Tyagi S. Orellana M. Kurley S.J. Dominguez-Vidaña R. al.Spliceosome-Targeted Therapies Trigger an Antiviral Immune Response Triple-Negative Breast Cancer.Cell. 2021; 184 January 14, 2021)https://doi.org/10.1016/j.cell.2020.12.031Abstract Full Text PDF (21) Scholar action for cancer. The authors report STT treatment cells with elevated errors promotes cytosolic accumulation intron-retaining (dsRNAs). STT-induced dsRNAs trigger signaling, extrinsic apoptosis, immune surveillance. Overall, this describes novel approach augment cancer immunogenicity. test two STTs, SD6 H3B-8800, component SF3B1 inhibit mRNA site recognition. currently advancing through FDA “investigational new drug” development, H3B-8800 progressing phase I clinical trials (NCT02841540). Experiments are predominantly conducted MYC-driven triple-negative breast (TNBC) lines, human mammary epithelial (HME1) inducible MYC-ER transgene, or HME1 acute degradation confirm on-target effects. first sought determine whether broad transcriptional changes provide insights into action. To examine transcriptome changes, sequencing (RNA-seq) STT- vehicle-treated TNBC cells. exhibit enrichment interferon (IFN) nuclear factor κB (NF-kB) sets 12–24 h post treatment. These trends recapitulated H3B-8800. Neither transgene expression nor isolation within Thus, innate restricted baseline defects. identify genes confer sensitivity resistance conduct forward genetic screen short hairpin (shRNA) library targeting signal-transducing proteins. top 50 shRNAs include numerous dsRNA components. Accordingly, immunofluorescence reveals induces accumulation. requires combination MYC overexpression cells, suggesting once again require Drug-induced leading response best characterized context epigenetic therapies, DNA demethylating agents (Roulois 2015Roulois D. Loo Yau H. Singhania Y. Danesh A. Shen S.Y. Han Liang G. Jones P.A. Pugh T.J. al.DNA-Demethylating Agents Target Colorectal Cancer Cells Inducing Viral Mimicry Endogenous Transcripts.Cell. 2015; 162: 961-973Abstract (611) Scholar), immunogenic derived from inverted Alu families interspersed elements (SINEs) often found introns (Mehdipour 2020Mehdipour P. Marhon S.A. Ettayebi I. Chakravarthy Hosseini de Castro F.A. Ishak C. Abelson al.Epigenetic therapy transcription SINEs ADAR1 dependency.Nature. 471: 169-173Crossref (33) components act independent retrotransposon content. Therefore, RNA-seq on poly(A)-containing characterize RNAs. enriches intronic long (LINEs) SINEs. immunoprecipitation followed poly(A) composed retained retrotransposons, Alus. Curiously, do not retrotransposons dsRNAs. observations suggest formation alerts system exceed certain threshold Activation sensing (Ishak 2018Ishak C.A. Classon De Carvalho D.D. Deregulation Retroelements Emerging Therapeutic Opportunity Cancer.Trends 2018; 4: 583-597Abstract (30) were clarified measuring activation specific caspases conducting systematic knockdowns individual sensors discover diverse pool stimulate multiple redundantly (Figure 1). Altogether, apoptosis involves but does exclusively depend any sensor adaptor. then use four orthotopic syngeneic murine models assess prompt H3B-8800-sensitive tumors distinguished intron retention higher relative resistant tumors. sensitive interferon-stimulated (ISG) levels. defects prime efficacy, correlates infiltration humans. Analysis TCGA datasets association between high T infiltration. Patients modest improvements disease-free survival. analysis reinforces experiment-derived toward Collectively, reviewed here suggests immunogenicity primed errors. involvement cull defective adds growing body literature implicates responses homeostasis maintenance. healthy example, alert exogenous viral infections. viruses endogenous editing mechanisms. edited adenosine-to-inosine enzyme prevent pathways translational shutdown. Individuals Aicardi-Goutières exacerbated IFN due MDA5 PKR. Ultimately, constitutive contributes inflammation associated neuropathies (Ahmad 2018Ahmad Mu X. Yang Greenwald E. Park J.W. Jacob Zhang C.-Z. Hur Breaching Self-Tolerance Duplex Underlies MDA5-Mediated Inflammation.Cell. 172: 797-810Abstract (156) Autoimmune conditions like underscore why must be tightly controlled checkpoint generally redundant involve fate decisions based stress stimuli thresholds. Beyond splicing, maintenance appears represent another emerging utilizes Functional machinery required heterochromatinize repeats permits subsequent mimicry. Circumvention mimicry ultimately tumorigenesis, perturbations facilitate oncogenesis represents mitigate initiation tumorigenesis presented draws several parallels sensing. Baseline MYC-induced insufficient activate absence treatment, tolerance death. Furthermore, immunity exhibits excessive redundancy, no single indispensable permit induction Among plethora questions borne study, perhaps most intriguing surround nature devoid retrotransposons. Thorough annotation further insight characteristics identity genomic source Undoubtedly, investigations will expand more well-characterized non-intronic sources dsRNAs, Scholar) 3′ untranslated regions (3′ UTRs) (Cañadas 2018Cañadas Thummalapalli Kitajima Jenkins R.W. Christensen C.L. Campisi Kuang Gjini al.Tumor retroviruses.Nat. Med. 24: 1143-1150Crossref (115) Determining crucial identifying contexts STT-based augmentation effective therapy. Identifying effectively emerged important consideration compounds recently discovered responses. For cyclin-dependent kinase 4/6 inhibitors retroviral intracellular levels lines (Goel 2017Goel DeCristo M.J. Watt A.C. BrinJones Sceneay J. Li B.B. Khan N. Ubellacker J.M. Xie Metzger-Filho O. al.CDK4/6 inhibition triggers anti-tumour immunity.Nature. 2017; 548: 471-475Crossref (515) Pharmacological also accompanied ISG enhanced blockade Efficacy nonsense RB1 suppressor Identification additional stratification criteria maximize drug efficacy characterization. Likewise, drug-resistant undergo rewiring establishes correctly matched therapies. both taxane- paclitaxel-resistant redistribute facultative heterochromatin intergenic normally repressed methylation (Deblois 2020Deblois Tonekaboni S.A.M. Grillo Martinez Kao Y.I. Tai Fortier A.-M. Savage Fedor A.N. Switch-Induced Evasion Chemotherapy-Resistant Cancer.Cancer Discov. 10: 1312-1329Crossref (23) Inhibition EZH2 histone methyltransferase results growth TNBCs. parallel similar erlotinib-resistant epidermal receptor mutant non-small-cell lung redistribution heterochromatinization drug-tolerant persister Heterochromatin these increase deacetylase young LINEs (Guler 2017Guler G.D. Tindell Pitti Wilson Nichols K. KaiWai Cheung T. H.J. Wongchenko Yan Haley B. al.Repression Stress-Induced LINE-1 Expression Protects Cell Subpopulations Lethal Drug Exposure.Cancer Cell. 32: 221-237Abstract (81) studies reinforce define maximum therapeutic effect, endeavor bring clinic. summary, generalized underlies anti-cancer properties STTs. increases intronic-retention cell-intrinsic Notably, cancer, progression Inherent transcript may combined immune-checkpoint blockades other highlights treatments D.D.D.C. received research funding Pfizer Nektar Therapeutics co-founder, shareholder, consultant DNAMx. declare competing interests Spliceosome-targeted cancerBowling al.CellJanuary 2021In BriefSpliceosome-targeted generate intron-retained, Full-Text