Table 1 Drugs targeting the BCR-ABL1-independent survival pathways
From: Chronic myeloid leukemia stem cells: targeting therapeutic implications
Drug | Target | Result | Reference |
|---|---|---|---|
Targeting autophagy | |||
Chloroquine (CQ) | Autophagy | Make CML LSCs susceptible to TKI-mediated apoptosis by blocking lysosome–autophagosome fusion and promoting cellular stress | [244] |
Spautin-1 |  Autophagy | Apoptosis of CML cells via inactivation of the PI3K/AKT pathway and downregulation of anti-apoptotic proteins | [245] |
Lys05 (A lysosomotropic drug) | Â Autophagy gene | Decrease in LSC quiescence and facilitation of myeloid cell growth | [246] |
PIK-III | The class III phosphatidylinositol 3-kinase, a vacuolar protein sorting 34 (VPS34) | Reduction of primary CML LSCs numbers | [246] |
Targeting surface antigens | |||
IL-1R antagonist | Interaction of interleukin 1 and its receptor | Inhibition of IL-1 signaling (NF-κB) and growth of CML LSC and also sensitize them to nilotinib | [247] |
Anti-IL-1RAP antibody | IL-1RAP: Co-receptor of the interleukin 1 receptor (IL1R1) | Killing CML cells and increase in survival of murine xenograft through inhibition of IL-1B signaling and induction of ADCC in CML | |
CAR T cell against IL1RAP |  IL-1RAP: Co-receptor of the interleukin 1 receptor (IL1R1) | Inhibition of IL-1 signaling (NF-κB) causing antileukemic effects | [250] |
vildagliptin | CD26 (DPP4) | Decrease in disease expansion through modulating the dysfunctional SDF1/CXCR4 axis to limit mobilization and niche escape of LSCs | [251] |
CAR T cells against CD26 | Â CD26 (DPP4) | Â Decrease in disease expansion through modulating the dysfunctional SDF1/CXCR4 axis to limit mobilization and niche escape of LSCs | [252] |
Drug-conjugated anti-CD33 antibody | CD33 | Death of most LSCs in CP-CML resulted from the quick internalization and release of the conjugated drug in the acidic environment of lysosomes and its binding to DNA, resulting in DNA double-strand breaks | |
Anti-CD44 antibody | CD44 | Inhibition of the adhesion to BMM and dormancy of the LSCs | [254] |
IL-3-toxin fusion protein SL-401 (Tagraxofusp) | IL-3R | Antileukemic activity by inhibition of cell growth and induction of cell apoptosis | |
CAR T cell against IL-3R (CD123) | Â IL-3R | Â Antileukemic activity by inhibition of cell growth and induction of cell apoptosis | |
Anti-CD70 antibody | CD70 (CD27L) | Decrease in expression of CD27 and WNT target genes leading to elimination of human CML progenitor/stem cells in combination with imatinib | [143] |
Targeting the interactions with BMM | |||
NOX-A12 | CXCL12 | Prevents LSCs homing and causes TKI sensitization | [259] |
Plerixafor (AMD3100) | CXCR4 | Â Prevents LSCs homing and causes TKI sensitization | [260] |
Acriflavine | HIF-1 | The antileukemic response by the modulation of STAT3/5 signaling Decrease in c-MYC and stemness-related genes (e.g., NANOG, SOX9, and OCT4), and increase in the expression of tumor suppressors (e.g., P57, P19Arf, and P16Ink4a) | [261] |
Thiazolidinediones (TZD) such as Pioglitazone (the anti-type 2 diabetic medication) | PPARγ | Reduction in the STAT5 activity Inhibition of LSC infiltration and localization to the BMM by upregulation of matrix metalloproteinase-9 (MMP-9) and MMP-2 Induction of LSC apoptosis by activation of caspase-3 | [182] |
Rosiglitazone |  PPARγ | Induction of LSC apoptosis associated with the increased expression of the stearoyl-CoA desaturase 1 (SCD1), phosphatase, and tensin homolog (PTEN), and P53 | [262] |
Clofazimine | Physical interaction with PPARγ to regulate its transcriptional activity | The induction of NF-kB-p65, resulting in P65 destruction, downregulation of peroxiredoxin-1 and increased ROS-induced apoptosis Proteasomal degradation Downregulation of dormancy and self-renewal of CML LSC by suppression of STAT5 expression and consequently downregulation of stem cell maintenance factors (HIF-1α/2α and CBP/P300/CITED2) | [263] |
Targeting signaling pathways | |||
Farnesyl transferase inhibitors (FT-Is) such as Tipifarnib and Lonafarnib | Protein farnesyltransferase | Preventing the proper functioning of the Ras | |
BP1001 (liposome-incorporated antisense oligodeoxynucleotide) | Growth factor receptor-bound protein 2 (GRB2) (a potent activator of ERK1 and ERK2) | Inhibition of RAS/MEK/ERK pathway | [185] |
Trametinib | MEK | Suppression of the MEK/ERK and NF-κB-mediated survival of CML LSCs | [186] |
ETC-1907206 | MAPK interacting protein 1 and 2 (MNK1/2) | Inhibition of the MAPK interacting protein 1 and 2 (MNK1/2)-eukaryotic initiation factor 4E (eIF4E) pathway and activation of β-catenin | [266] |
Dactolisib (NVP-BEZ235) | PI3K and mTOR | Inhibition of CML cell proliferation by triggering autophagy and apoptosis | [267] |
Pictilisib (GDC0941) | PI3K |  Inhibition of growth and survival of resistant CML cells by induction of apoptosis | [268] |
KU-0063794 | mTORC1/2 | Â Antiproliferative or proapoptotic effects by inhibiting activation of AKTÂ and other protein kinases | [268] |
Rapamycin (sirolimus) | mTOR | Induction of cell growth arrest and apoptosis and a reduction in cell proliferation | [269] |
Everolimus (RAD001) | Â mTOR | Â Induction of cell growth arrest and apoptosis and a reduction in cell proliferation | [270] |
Pimozide | STAT5 | A reduction in the proliferation of CML CD34+ cells induction of cell cycle arrest and apoptosis | [126] |
Ruxolitinib (RUB) | JAK2 | Decrease in JAK2/STAT5 activity, reactivation of PP2A | [121] |
Fedratinib (TG101348) | Â JAK2 | Â Decrease in JAK2/STAT5 activity, reactivation of PP2A | |
10,058-F4 | c-MYC | Promotion of an apoptosis by PP2A reactivation and modulation of autophagy | [273] |
OP449 | SET | Reactivate PP2A and apoptotic pathways in a PP2A-dependent manner leads to depletion of the LSCs by inhibiting STAT5 | [192] |
FTY720 | Â SET | Â Reactivate PP2A and apoptotic pathways in a PP2A-dependent manner leads to depletion of the LSCs by inhibiting STAT5 | [191] |
BP-5087 | STAT3 | Overcome independent survival and drug resistance of LSCs | [197] |
IFN-α | Activation of STAT1/5 | Differentiation and exhaustion of CML stem cells by the upregulation of FAS-R | [196] |
PRI-724 (ICG-001) | β-catenin/TCF mediated transcription (WNT/β-catenin signaling) | The disruption of the interaction between CBP and β/γ-catenin, leading to a decrease in self-renewal capability in leukemia-initiating cells in CML | |
Misoprostol | PGE1 | Activation of this PGE1-EP4 pathway and inhibition of TCF1/LEF1 and FOS/FOSB in WNT signaling | [132] |
Niclosamide | Interaction between the FOXM1/β-catenin/NF-Kb | Impairs the ability of CML LSCs to survive and self-renew | [200] |
WNT974 | PORCN (O-acyl transferase) | Inhibition of WNT signaling suppression of c-MYC, cyclin-D1 and Axin-2 expression, contributing to an increase in the inhibition of proliferation and eradication of CML stem cells | |
Cyclopamine | SMO | Eradicating Hh-mediated self-renewal capacity of CML LSC stimulates CML LSCs to cell cycle and become sensitive to TKIs | [202] |
LDE225 (sonidegib) | Â SMO | Â Eradicating Hh-mediated self-renewal capacity of CML LSC stimulates CML LSCs to cell cycle and become sensitive to TKIs | [203] |
Glasdegib (PF-04449913) | Â SMO | Â Eradicating Hh-mediated self-renewal capacity of CML LSC stimulates CML LSCs to cell cycle and become sensitive to TKIs | [204] |
Vismodegib | Â SMO | Â Eradicating Hh-mediated self-renewal capacity of CML LSC stimulates CML LSCs to cell cycle and become sensitive to TKIs | [205] |
Targeting energy metabolism | |||
SR-18292 | PPARγ coactivator-1α (PGC-1α) | Increase in PGC-1 acetylation, The downregulation of mitochondrial oxidative metabolism Increase in apoptosis of CML CD34+CD38– cells | [106] |
Tigecycline | mitochondrial metabolism | Impairment of mitochondrial protein synthesis and mitochondrial respiration | [56] |
Subutoclax | BCL2 | Disruption of energy metabolic pathways and decrease in oxidative phosphorylation levels, resulting in increase in CML LSCs eradication | |
Venetoclax | |||
LY25528 | BLT2 | Inhibition of ALOX15 pathway Inhibition of self-renewal in TKI-resistant CML cells by induction of apoptosis | [211] |
Zileuton | ALOX5 | Decrease in the survival of CML LSCs in mice | [33] |
QLT0267 | Integrin-linked kinase (ILK) | Induction of metabolic vulnerabilities by the reduction in the CD36 expression | [212] |
Targeting the epigenetic modification | |||
DS-5272 | MDM2 | The reactivation of P53, silencing ant-iapoptotic MCL-1 and sensitive quiescent CD34+ cells to therapy | [215] |
Panobinostat (LBH589) | HDAC | Increase in TKI-mediated apoptosis by acetylating HSP90 and increasing proteasomal degradation of key signaling proteins in CML LSCs | |
Chidamide |  HDAC | Induction of apoptosis by increasing acetylation of histone H3, activation of caspase 3/9, reduction in the β-catenin levels and its downstream targets surviving (a WNT–CBP–β-catenin-regulated gene), and c-MYC | |
MAKV-8 | Â HDAC | Reduction in the c-MYC expression and the stimulation of caspase 3/9 and ER stress, all of which contribute to LSC eradication | [219] |
Tenovin-6 | SIRT1 | Increase in apoptosis by increase acetylation of P53 | |
PJ-68 | PRMT5 | Induction of CD34+CD38− cell apoptosis by inhibiting the WNT/β-catenin pathway and inducing negative control on LSC renewal | |