Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia
Abstract
:Simple Summary
Abstract
1. Introduction
2. BCR::ABL1-Dependent Mechanisms of Resistance
2.1. Kinase Domain Mutations
Kinase Domain Mutations | TKI Sensitivity |
---|---|
T315I, Y253F/H, E255K/V, Q252H, M244V, L248V, G250E, F317L, M351T, M355D, F359V, and H396R/P/A | Reduced sensitivity to imatinib |
T315I, L248V, Y253H, E255K/V, and F359V/I/C | Reduced sensitivity to nilotinib |
T315I/A, V299L, and F317L/V/I/C | Reduced sensitivity to dasatinib |
T315I, E255V/K, V299L, G250E, E255K/V, and F317L/V/I/C | Reduced sensitivity to bosutinib |
T315M/L | Reduced sensitivity to ponatinib |
2.2. Myristoyl Domain Mutations
2.3. BCR::ABL1 Overexpression
2.4. Altered Expression of Drug Transporters
3. BCR::ABL1-Independent Mechanisms of Resistance/Persistence
3.1. Alternative Activation of MAPK Pathway
3.2. Alternative Activation of JAK/STAT Pathway
3.3. Alternative Activation of PI3K/AKT Pathway and Dysregulation of Autophagy
3.4. Activation of Wnt/β-Catenin Signalling
3.5. Protein Phosphatase 2A (PP2A) Level
3.6. Epigenetic Alterations
3.7. Inflammatory TNF-α and TGF-β Pathways
3.8. Sonic Hedgehog Pathway Activation
3.9. Dysregulation of Apoptotic Proteins’ Expression
4. Targeted Therapies against BCR::ABL1-Independent Resistant Cells
Target Pathway | Inhibitor/s | Stage of Development | Approved/Treated Disease | Ref. |
---|---|---|---|---|
RAS/RAF/MEK/ERK |
| FDA approved | BRAF(V600E) melanoma | [113] |
| FDA approved | |||
JAK/STAT |
| FDA approved |
| [114,115] |
| FDA approved |
| ||
| FDA approved |
| ||
PI3K/AKT/mTOR |
| FDA approved |
| [116,117] |
| FDA approved |
| ||
| FDA approved |
| ||
Wnt/β-catenin | CBP/β-catenin antagonist: PRI-724 | Phase 2 Clinical Trial (NCT01606579) | Acute myeloid leukaemia and chronic myeloid leukaemia | [118] |
Tumour suppressor: PP2A | SET: FTY720 (Fingolimod) | FDA Approved | Multiple myeloma and mantle cell lymphoma | [119,120] |
Epigenetic modulator: EZH2 | Tazemetostat | FDA Approved | Advanced or metastatic epithelioid sarcoma | [121] |
Immune system | IFN-α | FDA Approved | Hairy cell leukaemia, CML, follicular non-Hodgkin lymphoma, melanoma, and AIDS-related Kaposi’s sarcoma | [34] |
Hedgehog pathway | Vismodegib (GDC-0449) and Sonidegib (LDE225) | FDA Approved | Basal cell carcinoma and acute myeloid leukaemia | [122] |
Intrinsic apoptotic pathway | Venetoclax | FDA Approved | Chronic lymphocytic leukaemia and acute myeloid leukaemia | [123] |
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Poudel, G.; Tolland, M.G.; Hughes, T.P.; Pagani, I.S. Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia. Cancers 2022, 14, 3300. https://doi.org/10.3390/cancers14143300
Poudel G, Tolland MG, Hughes TP, Pagani IS. Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia. Cancers. 2022; 14(14):3300. https://doi.org/10.3390/cancers14143300
Chicago/Turabian StylePoudel, Govinda, Molly G. Tolland, Timothy P. Hughes, and Ilaria S. Pagani. 2022. "Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia" Cancers 14, no. 14: 3300. https://doi.org/10.3390/cancers14143300