Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia
Abstract
:1. Introduction
2. B Cell Receptor Signaling in Normal and Pathological Cells
3. Ibrutinib Mechanism of Action in CLL
4. Clinical Activity of Ibrutinib
5. Ibrutinib Adverse Events
6. Resistance Mechanisms and Clinical Implications
7. Alternative Irreversible BTK Inhibitors
7.1. Acalabrutinib
7.2. Zanubrutinib
7.3. Tirabrutinib
8. Reversible BTK Inhibitors
8.1. GDC-0853
8.2. Vecabrutinib (SNS-062)
8.3. LOXO-305
8.4. ARQ-531
9. Alternate Kinases Inhibitors and Drugs Potentially Overcoming Ibrutinib Resistance
9.1. Venetoclax
9.2. SYK Inhibitors
9.3. PI3K Inhibitors
9.4. Compound 1
9.5. Exportin-1 Inhibitors
9.6. Mammalian Target of Rapamycin (mTOR) Pathway Inhibition
9.7. Hsp90 Inhibition
9.8. Other Potential Molecules for BTKi-Resistant Patients
10. Chimeric Antigen Receptor T Cells
11. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Drug (Symbol) | Target | Mechanism | Advantage Over Ibrutinib | Phase and Clinical Trial Number | Head to Head Comparison to Ibrutinib |
---|---|---|---|---|---|
Acalabrutinib (ACP-196) | BTK | Irreversible and covalent inhibitor | Minimal off-target inhibitory activity, no anti-platelet activity, effective to ibrutinib intolerance | III NCT04008706 | NCT02477696 |
Zanubrutinib (BGB-3111) | BTK | Irreversible and covalent inhibitor | Less inhibitory to ITK | III NCT04116437 NCT03336333 | NCT03734016 |
Tirabrutinib (ONO/GS-4059) | BTK | Irreversible, covalent inhibitor | Less inhibitory to TEC | III NCT02457559 | No |
GDC-0853 | BTK | Reversible, non-covalent inhibitor | Overcomes C481S mutation, effective to ibrutinib resistance | I NCT01991184 | No |
Vecabrutinib (SNS-062) | BTK | Reversible, non-covalent inhibitor | Overcomes C481S mutation, effective to ibrutinib resistance, less inhibitory to EGFR | I/II NCT03037645 | No |
LOXO-305 | BTK | Reversible, non-covalent | Overcomes C481S mutation | I/II NCT03740529 | No |
ARQ-531 | BTK LYN MEK | Reversible, non-covalent | Overcomes C481S and PLCG2 mutations | I/II NCT03740529 | No |
Entospletinib (GS-9973) | SYK | ATP-competitive, selective inhibitor | Overcomes PLCG2 mutations | II NCT01796470 NCT01799889 | No |
Cerdulatinib (PRT062070) | SYK/JAK | ATP-competitive inhibitor | Overcomes C481S mutation and inhibits microenvironment support for CLL cells | I/II NCT01994382 | No |
Duvelisib (IPI-145) | PI3Kγ PI3Kδ | ATP-binding region | Inhibits microenvironment support for CLL cells | III NCT02004522 | No |
Selinexor (KPT330) | XPO-1 | Reversible, covalent inhibitor | Overcomes C481S mutation, suppresses BTK gene, inhibits activation of downstream BCR targets ERK and AKT | II NCT02227251 | No |
CC-115 | mTOR | Inhibits auto-phosphorylation of the catalytic site | Overcomes ibrutinib resistance | I NCT01353625 | No |
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Puła, B.; Gołos, A.; Górniak, P.; Jamroziak, K. Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia. Cancers 2019, 11, 1834. https://doi.org/10.3390/cancers11121834
Puła B, Gołos A, Górniak P, Jamroziak K. Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia. Cancers. 2019; 11(12):1834. https://doi.org/10.3390/cancers11121834
Chicago/Turabian StylePuła, Bartosz, Aleksandra Gołos, Patryk Górniak, and Krzysztof Jamroziak. 2019. "Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia" Cancers 11, no. 12: 1834. https://doi.org/10.3390/cancers11121834