Table 2.
Therapy resistance conferred by epithelial-to-mesenchymal transition (EMT)
| Therapeutic agent | Observations | Refs |
|---|---|---|
| Inhibition of apoptotic signalling | ||
| Cisplatin | Slug blocks p53-mediated transcriptional induction of PUMA (also known as BBC3, encoding Bcl-2-binding component 3) expression by directly repressing the PUMA promoter region; multiple lung adenocarcinoma cell lines acquire cisplatin resistance through this mechanism | 195,196 |
| Tumour necrosis factor α (TNFα) treatment; γ-irradiation | Snail confers resistance against multiple apoptosis-inducing stimuli, in part by promoting AKT activation, upregulating the expression of the pro-survival protein Bcl-XL, and delaying cell-cycle progression | 197,198 |
| TNF-related apoptosis-inducing ligand (TRAIL) | EMT-programme activation diminishes E-cadherin-mediated clustering of the TRAIL receptors DR4 and DR5, thereby making carcinoma cells resistant to TRAIL-induced apoptosis | 199 |
| Enhancement of drug efflux | ||
| Doxorubicin | EMT-programme activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, thereby rendering these cells resistant to doxorubicin. | 200 |
| Protection against molecular targeted agents | ||
| EGFR inhibitors | The activation of EMT and subsequent expression of AXL receptor tyrosine kinase confer resistance to EGFR inhibitors onEGFR-mutant non-small-cell lung carcinoma (NSCLC) cells | 201,202 |
| EGFR inhibitors; PI3K inhibitors | An EMT-associated gene-expression signature predicts the resistance of NSCLC cells to EGFR inhibitors and PI3K inhibitors | 163 |
| Desensitization to immunotherapy | ||
| Dendritic cell (DC)-mediated immunotherapy (intratumoral injection of DCs pulsed with a tumour antigen) | Snail expression in melanoma cells contributes to resistance to DC-mediated and CTL-mediated immunotherapy via enhanced thrombospondin-1 expression and resultant induction of immunosuppressive regulatory T cells within the tumour tissue | 203 |
| Immune-checkpoint inhibition | Zinc finger E-box-binding homeobox (ZEB1)-mediated activation of EMT in NSCLC cells relieves miR-200-mediated repression of programmed cell death 1 ligand 1 (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein 1 (PD-1) immune-checkpoint protein on CD8+ CTLs. This effect sensitizes these cells to immunotherapies targeting the PD-1 PD-L1 axis, while potentially conferring on them resistance to other strategies of activating antitumour immunity, such as the functional blockade of another immune-checkpoint protein, CTLA-4 | 204 |