Table 1.
Major aberrant pathways and associated emerging systemic therapies for advanced MF/SS.
| Pathway | Gene | Systemic agent class | Agent name | Mechanism of action | References |
|---|---|---|---|---|---|
| TCR Signalling | PLCG1 | PLCG1 inhibitor | In development | Inhibition of PLCG1 leading to decreased TCR signalling | -- |
| CD28 | |||||
| CARD11 | |||||
| PRKCB/Q | PKCθ inhibitor | Sotrastaurin | Inhibition of STAT3, leading to decreased cell proliferation and apoptosis in pre-clinical studies. | Garcia-Diaz (15) | |
| RLTPR | |||||
| PTPRN2 | |||||
| JAK-STAT pathway | JAK1-3 | JAK inhibitor | Ruxolitinib | JAK1/2 inhibitor. Dysregulated JAK-STAT pathway in CTCL leads to T-cell activation. Phase II trial showed 23% ORR. | Moskowitz (16) |
| STAT3-5 | |||||
| DNA Damage Repair | ATM | ATR inhibitor | VE-821/2 ETP-46464 AZD6738 |
Synthetic lethality in view of HR defects. Decreased cell viability in SS cells and increased sensitivity to phototherapy in CTCL cell lines in pre-clinical studies. | Biskup (17) Pinzaru (3) |
| BRCA1/2 | |||||
| RAD50/51C | |||||
| Chk2 | |||||
| POT1 | |||||
| Chromatin Modification | TET2 | HDAC inhibitor | Resminostat Vorinostat Romidepsin |
HDACi modify acetylation sites in proteins leading to dysregulated gene transcription, cell cycle arrest and apoptosis. Resminostat phase II trial ongoing (RESMAIN NCT02953301). Vorinostat and Romidepsin are FDA and EMA approved. | Olsen (18) Whittaker (19) |
| ARID1A/B | |||||
| DNMT3A | |||||
| SMARCB1 | |||||
| SETDB2 | |||||
| TRRAP | |||||
| CREBBP | |||||
| NCOR1 | |||||
| BCOR | |||||
| CTCF | |||||
| KMT2C-D | |||||
| Cell cycle | CDKN2A | -- | -- | -- | -- |
| TP53 | |||||
| NFkB pathway | TNFRSF1B | Proteasome inhibitor | Bortezomib | Inhibits the degradation of the nuclear factor kappa B (NFκB) inhibitor IκBα. Phase II trial showed 67% ORR. | Zinzani (20) |
| NFKB2 | |||||
| PRKCB | |||||
| TNFAIP3 | |||||
| IRF4 | |||||
| CSNK1A1 | |||||
| T-cell migration | CCR4 | CCR4 antibody | Mogalizumab | Increased CCR4 expression seen in CTCL. Phase III trial (MAVORIC) of CCR4 inhibitor leads to increased PFS and OR vs. Vorinostat in SS. | Kim (21) |
| MAPK pathway | NF1 | -- | -- | -- | -- |
| RAS | |||||
| BRAF | |||||
| MAP2KI | |||||
| MAPK1 | |||||
| PI3K pathway | VAV1 | Phosphatidylinositol 3-kinase (P13K) inhibitor | Duvelisib | PI3K-δ and PI3K-γ active in leucocytes and important for modulating immune response and tumour microenvironment. Phase I trial showed 32% ORR. | Horwitz (22) |
| ARHGEF3 | |||||
| RHOA | |||||
| PD-1 pathway | PRKCB | Anti-PD1/PD-L1 inhibitors | Pembrolizumab Nivolumab |
Increased PD-1 expression in CTCL. Inhibition enhances cytotoxic T-cell killing. Phase II trial showed 38% ORR. | Khodadoust (23) |
| PD-L1 | |||||
| PD-L2 |
A summary of the main pathways harbouring putative driver gene mutations or copy number changes in MF/SS. Novel systemic therapies targeting these pathways currently under investigation are also highlighted. FDA, US Food and Drug Administration; EMA, European Medicines Agency.