Table 3 Treatment targets with alternative splicing.
From: Alternative splicing of mRNA in colorectal cancer: new strategies for tumor diagnosis and treatment
Agents | Splicing gene | Direct targets | Mechanism | Stage of development | Referrence |
|---|---|---|---|---|---|
SSO | BCLAF1 | 3’SS at the boundary of intron 4 and exon5a | SSO treatment increase truncated isoform against SRSF10 splicing effect and inhibits cell proliferation. | Preclinical Cell level | [61] |
SSO | PKM | SSO against exon 10 for PKM | The SSO against exon 10 for PKM gene decreased the mRNA ratio of PKM2/PKM1. | Preclinical Cell level | |
SSO | DVL | 3′SS of intron 2 of DVL2 | The increasing intron2 retention variant for DVL2 can inhibits cell proliferation whether SETD2 exists or not. | Preclinical Cell level | [46] |
SSO (2′-OMe phosphorothioation) | HnRNP A1 | Blocking 5′ SS of SMN2 exon 7 | The SSOs targeted hnRNP A1 binding sites of SMN exon 7 and then reduced oncogenic exon 7 inclusion variant to inhibit CRC. | Preclinical Cell level | |
RHPS4, G4 structures | CD133 | The 118 bp upstream and 261 bp downstream of acceptor sites of exons 4 and 7 | RHPS4 treatment increase intron3,6 retention variant with early termination of translation, then cause more truncated isoform CD133 and surpress cell growth. | Preclinical Cell level Mice level | [121] |
Prodigiosin | P73 | Upregulated c-Jun, and induced phosphorylation of c-Jun | Prodigiosin induces phosphorylation of c-Jun, which mediates p73 upregulation and ΔNp73 downregulation and then inhibited the growth of xenograft tumors initiation. | Preclinical Cell level Mice level | [117] |
Ibrutinib (BTK) AVL-292(BTK) | BTK | BTK kinase inhibitor | The inhibitor of P65BTK oncogeneic isoform depends on p-hnRNPK, which is active by ERK1/2 and RAS. | Preclinical Cell level | [119] |
FTI-277 (RAS) CI-1040 (MEK1/2) | Inhibitor of hnRNPK phosphorylation | ||||
Nilotinib (ZAK inhibitor) | ZAK | Inhibitor of ZAK-autophosphorylation and auto-activation | Nilotinib suppresses pro-tumoral reaction cascades of ZAKs, which are key factors in cancer cell migration. | Preclinical Cell level | [118] |
Bay 11-7082 (NF-κB inhibitor) | TXL2 | NF-κB(downstream of oncogenic TXL-2b variants) | Txl-2b contributes to resistance against vincristine and induces apoptosis by activating NF-κB signaling and blocking the downstream. | Preclinical Cell level | [120] |
SSO(locked nucleic acid, LNA) | Aurora-A | Target exon 2-containing Aurora-A 5’-UTR | SSO targets the carcinogenic exon 2-containing Aurora-A mRNA isoforms can inhibit tumor growth. | Preclinical Cell level Mice level | [136] |
SSO (antisense morpholino oligomer) | VEGFR | Against 5’SS of exon13-intron13 junction | SSO is directed against the junction sequence that shifts expression from mVEGFR2 to the antiangiogenic sVEGFR. | Preclinical Cell level | [91] |
10058-F4(MYC inhibitor) | ITGA6 | MYC inhibitor | MYC inhibitor increases the epithelial splicing regulatory protein 2 (ESRP2) and decreases the tumor promoter ITGA6a variant. | Preclinical Cell level Mice level | [115] |
SB21673(GSK3β inhibitor) | Inhibiting GSK3β kinase activity | The inhibitor can suppress ITGA6A variant, which interferes with the Wnt/β-catenin pathway by enhancing phosphorylation of β-catenin by GSK3β. | [137] | ||
SM08502 small molecular inhibitor | DVL2, ERBB2, LRP5, TCF7 | Inhibitor of CLKs | SM08502 inhibits SRSF phosphorylation and disrupts spliceosome activity, which inhibits of Wnt pathway-related gene and expression of splicing regulator. | Preclinical Cell level Mice level Phase 1 clinical trial (NCT03355066) | [116] |
SSO(Dex8-VDR oligomer SA (+12)) | VDR | SSO target splice acceptor site of exon8 | SSO targets splice acceptor site of exon8 and alters VDR signaling cascades for treatment. | Preclinical Cell level | [109] |
Nicotinamide(NAM):(HDAC I and II inhibitors) | KDM3A | Block the kinase activity of HDAC to decrease PHF5A acetylation | The acetylated PHF5A interacts with U2 snRNP complex and reduces aberrant splicing of KDM3A and the inhibitor blocks PHF5A acetylation. | Preclinical Cell level | [70] |
FR901464(Small molecular inhibitor) | – | FR901464 competitively binds to SF3B1 | The inhibitor binds with and inhibits SF3B1 and destabilizes the recruitment of snRNP U2 and spliceosome assembly to decreases cell proliferation and tumor growth. | Preclinical | [114] |
Pladienolide B | SF3B1 | Inhibitor of SF3B1 assembly | The inhibitor promotes cell apoptosis by the alternative use of two 5’ SS regions in exon 2 and increases BCL-xs isoform. | Preclinical | |
E7107 | SF3B1 | Inhibitor of SF3B1 assembly | The inhibitor reduced remodeling U2 snRNP to expose the branch point-binding region and then inhibits tumor growth. | Phase 1 clinical trial | [138] |
Indacaterol (SRSF6 inhibitor) | ZO-1 | Binding to RRM2 domain of SRSF6 | The inhibitor can reduce RRM2 binding to ZO-1 exon23 and suppress CRC tumourigenicity. | Preclinical Cell level Mice level | [59] |
