Table 1.
A compendium of ncRNA-related targets and mechanisms in resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy
| Human ncRNA | Expression: down- or upregulated; cancer type | Function in therapy resistance | Molecular mechanisms and targets | Ref |
|---|---|---|---|---|
| Resistance to chemotherapy | ||||
| CCAT2 | Upregulated in MSS (CIN) CRC | High levels are associated with resistance to 5-fluorouracil and oxaliplatin | Binds to BOP1 and AURKB, increasing aberrant mitosis and abnormal karyotypes | 50 |
| MACC1-AS1 | Overexpressed in FOLFOX-resistant GC | High levels activate fatty acid oxidation pathway | Binds miR-145-5p, derepressing CPT1 and ACS | 51 |
| MiR-27a | Downregulated in cisplatin-resistant bladder cancer | Low levels are associated with increased glutathione production that detoxifies the intracellular milieu | Binds SLC7A11 and inhibits its translation | 52 |
| CircAKT3 | Upregulated in cisplatin-resistant gastric cancer | High levels are associated with cisplatin resistance and increased DNA damage | Binds miR-198, derepressing PIK3R1 and consequentially activating the PI3K/AKT signaling pathway | 53 |
| Resistance to targeted therapy | ||||
| LncARSR | Upregulated in tissue and plasma of renal cell carcinoma patients with sunitinib resistance | Induces sunitinib residence that is transferable between cells | Binds miR-449 and miR-34a, indirectly upregulating AXL and c-MET | 56 |
| MIR100HG (miR-100, miR125b) | Upregulated in CRC and HNSCC cells and CRC patients at time of progression on cetuximab | Activated at time of progression on cetuximab | The two miRNAs activate the Wnt signaling pathway by inhibiting five of its negative regulators: DKK1, DKK3, ZNRF3, RNF43, and APC | 57 |
| MiR-541 | Upregulated in HCC with long overall survival, high in HCC patients who responded to sorafenib | High levels in an additive manner increase the anti-tumorigenic effect of sorafenib | Inhibits autophagy via directly inhibiting RAB1B and ATG2A | 59 |
| CircRNA-SORE | Upregulated in HCC, higher in patients treated with sorafenib who had short RFS | Induces sorafenib residence that is transferable between cells | Binds to and prolongs the half-life of the oncoprotein YBX1 by preventing its degradation | 60 |
| Resistance to radiotherapy | ||||
| Linc00312 | Overexpressed in chronic rhinitis versus nasopharyngeal carcinoma | Blocks the DNA double-stand break repair machinery | Directly binds DNA-PKcs and inhibits its interaction with Ku80 | 63 |
| MiR-410 | High levels are associated with radioresistance in NSCLC | Enhances the DNA damage repair machinery upon irradiation | Directly binds and inhibits PTEN, indirectly activating the PI3K/mTOR pathway | 65 |
| MiR-139-5p | Downregulated in breast cancer patients who experience relapse after radiotherapy | High levels of miR-139-5p inhibit DNA repair genes and ROS defense mechanism | Directly binds and inhibits the translation of MAT2A, POLQ, TOP1, and TOP2A | 64 |
| CircAKT3 | Downregulated in GBM | Low levels are associated with radioresistance | Encodes for a 174 aa protein, which inhibits the phosphorylation of AKT at Thr308 | 66 |
| Resistance to immunotherapy | ||||
| LINK-A | Upregulated in TNBC patients who do not respond to pembrolizumab | Decreases the number of tumor-infiltrating CD8+ and NK cells | Induces degradation of the antigen peptide-loading complex, TP53 and Rb. | 69 |
| MiR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, and miR-99b | Upregulated in plasma EVs from advanced stage melanoma patients | Increase the number of tumor-infiltrating myeloid cells | Induce the transformation of monocytes into MDSCs | 71 |
| CircMET | Upregulated in HCC, associated with unfavorable outcomes | Induces anti-PD-1 residence by decreasing intratumoral CD8+ cells | Sponges miR-30-5p, derepressing Snail, which indirectly inhibits CXCL10 via DPP4 | 72 |
| CircUHRF1 | Upregulated in HCC, associated with unfavorable response to anti-PD-1 therapy | Induces anti-PD-1 residence by suppressing NK cell function | Sponges miR-449c-5p, indirectly activating the immune checkpoint molecule TIM-3 | 73 |
CIN Chromosomal instability; CRC Colorectal cancer; DNA-PKcs DNA-dependent protein kinase catalytic subunit; EV Extracellular vesicles; FOLFOX Folinic acid, fluorouracil, and oxaliplatin; GC Gastric cancer; GBM Glioblastoma multiforme; HCC Hepatocellular carcinoma; HNSCC Head and neck squamous carcinoma; MDSC Myeloid-derived suppressor cells; MSS Microsatellite stable; NSCLC Non-small cell lung cancer; RFS Recurrence-free survival; TNBC Triple-negative breast cancer.