Table 1.
Therapeutic targets and drugs to overcome therapy resistance mechanisms in AML (stem) cells.
| AML (stem) cell therapy resistance mechanism | Target protein or process | Drug | Preclinical studies | Clinical trial for AML | References |
|---|---|---|---|---|---|
| Quiescence | miR-126 | N/A | Reduction of clonogenic capacity of LSCs in the absence of an inhibitory effect on normal BM cells. | N/A | (42, 43) |
| PI3K/Akt; PTEN | Rapamycin | Depletion of leukemia-initiating cells and restoration of normal HSC function. | - Phase I: rapamycin + decitabine in r/r AML - Phase I: rapamycin + chemotherapy in newly diagnosed AML, r/r AML and secondary AML - Phase II: rapamycin in r/r AML |
(44, 45) | |
| FOXM1 | Thiostrepton | Reduction of self-renewal capacity of LSCs in MLL-rearranged AML, synergistic effects with chemotherapy on induction of apoptosis in LSCs, and prolonged survival in vivo. | N/A | (46) | |
| Epigenetically driven drug resistance | LSD1 | Iadademstat (ORY-1001) |
LSD1 target gene specific increase of H3K4me2, induction of AML blast differentiation and reduction of LSC self-renewal capacity, while sparing normal CD34+ cells. | Phase I/IIa in r/r AML (non-M3) and r/r MLL-rearranged AML | (47–49) |
| TCP | Induction of differentiation of AML blasts and inhibition of AML cell growth. | Phase I/II: ATRA + TCP in r/r AML (non-M3) | (50, 51) | ||
| GSK-LSD1 | Myeloid differentiation in MLL-rearranged AML cells, causing global gains in chromatin accessibility, with an enrichment of PU.1 and C/EBPα at these open sites. | N/A | (52) | ||
| EZH2 and/or EZH1 | DZNEP | Reduced EZH2 and H3K27me3 levels, resulting in reduced CD34+CD38- LSC numbers. In combination with panabinostat, synergistic induction of apoptosis in AML cells, while sparing normal CD34-positive BM progenitor cells. | N/A | (53, 54) | |
| OR-S1 | Reduction of LSC numbers, impaired AML progression and prolonged survival in vivo. Priming AML cells for chemotherapy-induced cell death. | N/A | (55) | ||
| Valemetostat (DS-3201) |
Recruitment of quiescent AML LSCs into cell cycle. | Phase I in r/r AML | (56) | ||
| G9a | CM-272 | Activation of interferon response, inhibiting proliferation and promoting apoptosis. Prolongation of OS in AML xenogeneic mouse models. | N/A | (57) | |
| Pinometostat (EPZ5676) | Tumor growth suppression, reduced colony-forming capacity, and terminal differentiation in DNMT3A-mutated AML cells. | Phase I in MLL-rearranged AML | (58, 59) | ||
| BET proteins | JQ1 | Anti-leukemic effects accompanied by terminal differentiation and elimination of LSCs. Reduction of BCL2 and c-myc levels, inducing apoptosis in NPM1c+ with or without FLT3-ITD or MLL-rearranged AML. In combination with panabinostat, synergistic induction of apoptosis in AML, while sparing normal CD34-positive BM progenitors. | N/A | (60, 61) | |
| Birabresib (OTX015) | Inhibition of cell growth, cell cycle arrest and apoptosis in AML cells. | Phase I in r/r AML | (62) | ||
| Molibresib (GSK525762) |
Downregulation of BCL2, c-myc and IRF8, reduction in clonal growth and induction of apoptosis in AML cells, and survival advantage in vivo. | Phase I/II in r/r AML and secondary AML | (63) | ||
| Hypoxia and metabolism | BCL2 | Venetoclax | Inhibition of OXPHOS and impairing energy homeostasis, upregulation of myeloid differentiation genes, and downregulation of cell cycle and proliferation genes. | Phase Ib and phase III: venetoclax + azacitidine in elderly AML Phase Ib: venetoclax + azacitidine or decitabine in elderly AML Phase II: venetoclax in r/r AML Phase III: venetoclax + cytarabine in newly diagnosed AML ineligible for intensive chemotherapy |
(13–17, 64, 65) |
| MCL-1 | (−)BI97D6 | Induction of mitochondrial apoptosis in AML, due to disrupted MCL-1/BIM and BCL2/Bax interactions, while sparing normal hematopoietic stem/progenitor cells. | N/A | (66) | |
| VU661013 + venetoclax | Destabilization of BIM/MCL1 and induction of apoptosis in AML. Synergistic reduction in tumor burden after combination therapy. | N/A | (67) | ||
| AZD5991 | Induction of apoptosis in AML by activation of Bak-dependent mitochondrial apoptosis, and anti-tumor activity. | Phase I/II: AZD5991 monotherapy or in combination with venetoclax in r/r AML | (68) | ||
| AMG176 | Rapid induction of apoptosis in AML, growth inhibition of human AML in vivo. | Phase I: AMG176 + azaciditine in r/r AML | (69) | ||
| MIK665 (S64315) |
Induction of AML cell death, induction of antitumor responses after combination treatment with a BCL2 inhibitor. | Phase I: S64315 in r/r AML (non-M3) Phase I: VOB560 (BCL2 inhibitor) + S64315 in r/r AML |
(70) | ||
| HIF-1α | Echinomycin | Inhibition of colony formation, induction of apoptosis of CD34+CD38- AML cells. Elimination of leukemia initiating cells and reduction in human leukemic burden. | N/A | (71) | |
| TH-302 | Hypoxia-dependent apoptosis in AML cells, by reducing HIF-1α expression, decreasing proliferation, inducing a cell-cycle arrest, and enhancing double-stranded DNA breaks. Prolongation of residual disease after chemotherapy treatment in vivo. | N/A | (72, 73) | ||
| Bone marrow micro-environment | CXCR4 | Plerixafor (AMD3100) | Mobilization of AML blasts from the BM niche into peripheral circulation, sensitization of leukemic blasts to cytarabine and decreased tumor burden in vivo. | Phase I/II: plerixafor + mitoxantrone, etoposide and cytarabine in r/r AML Phase I/II: plerixafor + decitabine in newly diagnosed elderly Phase I/II: plerixafor + fludarabine, idarubicin, cytarabine and G-SCF in r/r AML |
(74–76) |
| ARV-825 | CXCR4 and CD44 downregulation, impairment of CXCL12-directed migration, increased oxidative stress, downregulation of gene signatures associated with stemness, Wnt/β-catenin and Myc pathways, and decrease in number of LSCs. | N/A | (77) | ||
| TGFβ | 1D11 | Enhanced cytarabine-inducted apoptosis of AML cells in hypoxic conditions. Combination treatment with plerixafor and cytarabine decreased leukemia burden in FLT3-mutated mice. | N/A | (78) | |
| VEGF-C | VGX-100 | Reduction of clonogenic capacity and induction of differentiation of AML blasts, via suppression of FOXO3A and inhibition of MAP/ERK proliferative signals. | N/A | (79) | |
| Bevacizumab | N/A | Phase I: bevacizumab n r/r AML Phase II: bevacizumab + mitoxantrone + cytarabine in r/r AML Phase II: bevacizumab + daunorubicin + cytarabine in newly diagnosed elderly |
(80) (81, 82) |
||
| Adipocytes | FABP4 | BMS309403 | Inhibition of AML blast survival, while sparing nonmalignant CD34-positive cells. | N/A | (83) |
| FAO | Etomoxir | Disruption of metabolic homeostasis in AML cells, induction of ROS production and ATF4. Inhibition of CPT1a and subsequent sensitization of AML cells to cytarabine. Induction of an energetic shift towards low OXPHOS and increase in anti-leukemia effects of cytarabine. | N/A | (36) (84) (85) |
|
| Avocatin B | Upregulation of ATF4 and synergistic induction of ROS production and apoptosis in AML cells after combination treatment with cytarabine. | N/A | (84) | ||
| Stress response | Autophagy | VSP34 inhibitors | Inhibition of autophagy and cell proliferation abolishes acquired FLT3 inhibitor resistance. | N/A | (86) |
| PERK/eIF2α pathway | Atovaquone | Phosphorylation of eIF2α, enhancing ATF4 protein expression and ATF4-specific target genes, inhibiting OXPHOS, and inducing growth arrest and apoptosis in AML cells. | N/A | (87) | |
| GSK2606414 + BIX-01294 | Synergistic induction of apoptosis in AML cells, while sparing normal HSCs. | N/A | (88) |
LSC, leukemic stem cell; HSC, hematopoietic stem cell; BM, bone marrow; r/r AML, relapsed and refractory acute myeloid leukemia; OS, overall survival; ROS, reactive oxygen species; oxidative phosphorylation, OXPHOS, N/A, not applicable.