Candidate therapeutic targets in CP CML LSCs
| Target or survival factor . | Pathway . | Exemplar inhibitors/activators . | Reference . | CML clinical trial . |
|---|---|---|---|---|
| ALOX15 | β-catenin; PI3K/AKT signaling | PD146176 | 106 | No |
| ALOX5 | Wnt/β-catenin signaling | Zileuton | 69 | Yes |
| Autophagy | Autophagy | Chloroquine; bafilomycin A1 | 113 | Yes |
| As2O3 | ||||
| 114 | ||||
| 115 | ||||
| BCL6 | PI3K/AKT/FOX3a/BCL6 signaling | RI-BPI | 56 | No |
| BLK | MYC/PAX5/BLK/CDKN1B signaling | NA | 116 | No |
| CCN | Wnt/Ca2+/NFAT signaling | Cyclosporin A | 68 | No |
| CD25 | JAK/STAT signaling | BEZ235 | 111 | No |
| CD70/CD27 | Wnt/β-catenin signaling | αCD70 mAb | 67 | No |
| c-MYC and TP53 | apoptosis | CPI-203; RITA/RG7388 | 98 | No |
| EZH2 | Histone H3 K27 trimethylation | GSK 343; GSK126 | 101 | No |
| EPZ-6438 (tazemetostat) | 100 | |||
| Farnesyl transferases | RAS signaling; protein farnesylation | BMS-214662 | 117 | Yes |
| FOX03A | TGF-β/AKT/FOXO3a/BCL6 signaling | NA | 57 | No |
| 58 | ||||
| GSK3β | Wnt/β-catenin signaling | SB216763 | 118 | No |
| HDACs | Histone acetylation | LBH589 | 119 | Yes |
| JAK2 | JAK/STAT signaling | Ruxolitinib | 74 | Yes |
| PML | Apoptosis; mTOR repression | As2O3 | 120 | Yes |
| PP2A | JAK/STAT/β-catenin signaling | 1,9-dideoxy-forskolin; FTY720 | 76 | No |
| 77 | ||||
| PPARγ | STAT5/HIF2α/CITED2 | Pioglitazone | 102 | Yes |
| 103 | ||||
| RAD52 | DNA repair | RAD52 F79 peptide aptamer | 82 | No |
| SIRT1 | Deacetylation of p53 | Tenovin-6 | 121 | No |
| SMO | Hedgehog signaling | Cyclopamine; LDE225 | 60 | Yes |
| 61 | ||||
| 62 | ||||
| STAT3 | JAK/STAT signaling | BP-5087 | 80 | No |
| TGF-β RI, ALK5 | TGF-β/AKT/FOXO3a/BCL6 signaling | Ly364947; EW-7197 | 58 | No |
| 122 |
| Target or survival factor . | Pathway . | Exemplar inhibitors/activators . | Reference . | CML clinical trial . |
|---|---|---|---|---|
| ALOX15 | β-catenin; PI3K/AKT signaling | PD146176 | 106 | No |
| ALOX5 | Wnt/β-catenin signaling | Zileuton | 69 | Yes |
| Autophagy | Autophagy | Chloroquine; bafilomycin A1 | 113 | Yes |
| As2O3 | ||||
| 114 | ||||
| 115 | ||||
| BCL6 | PI3K/AKT/FOX3a/BCL6 signaling | RI-BPI | 56 | No |
| BLK | MYC/PAX5/BLK/CDKN1B signaling | NA | 116 | No |
| CCN | Wnt/Ca2+/NFAT signaling | Cyclosporin A | 68 | No |
| CD25 | JAK/STAT signaling | BEZ235 | 111 | No |
| CD70/CD27 | Wnt/β-catenin signaling | αCD70 mAb | 67 | No |
| c-MYC and TP53 | apoptosis | CPI-203; RITA/RG7388 | 98 | No |
| EZH2 | Histone H3 K27 trimethylation | GSK 343; GSK126 | 101 | No |
| EPZ-6438 (tazemetostat) | 100 | |||
| Farnesyl transferases | RAS signaling; protein farnesylation | BMS-214662 | 117 | Yes |
| FOX03A | TGF-β/AKT/FOXO3a/BCL6 signaling | NA | 57 | No |
| 58 | ||||
| GSK3β | Wnt/β-catenin signaling | SB216763 | 118 | No |
| HDACs | Histone acetylation | LBH589 | 119 | Yes |
| JAK2 | JAK/STAT signaling | Ruxolitinib | 74 | Yes |
| PML | Apoptosis; mTOR repression | As2O3 | 120 | Yes |
| PP2A | JAK/STAT/β-catenin signaling | 1,9-dideoxy-forskolin; FTY720 | 76 | No |
| 77 | ||||
| PPARγ | STAT5/HIF2α/CITED2 | Pioglitazone | 102 | Yes |
| 103 | ||||
| RAD52 | DNA repair | RAD52 F79 peptide aptamer | 82 | No |
| SIRT1 | Deacetylation of p53 | Tenovin-6 | 121 | No |
| SMO | Hedgehog signaling | Cyclopamine; LDE225 | 60 | Yes |
| 61 | ||||
| 62 | ||||
| STAT3 | JAK/STAT signaling | BP-5087 | 80 | No |
| TGF-β RI, ALK5 | TGF-β/AKT/FOXO3a/BCL6 signaling | Ly364947; EW-7197 | 58 | No |
| 122 |
Column 1 indicates key survival factors/drug targets intrinsic to the LSC. Column 2 lists the roles of these factors/targets in cellular pathways (if known or as proposed by investigators). Column 3 shows exemplar compounds that have been identified as having potential therapeutic value for each factor/target or pathway (if known). Column 4 provides the references in which the factors/targets are described. Column 5 indicates whether factors/targets or compounds have been evaluated in clinical trials.
As2O3, arsenic trioxide; NA, not available.