Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update
Abstract
:1. Introduction
2. Neuroblastoma
2.1. Aetiology, Prevalence and Characteristics
2.2. Risk Factors, Tumour Staging and Treatment
3. ALK in Health and Disease
3.1. Structure and Function of ALK
3.2. The Role of ALK in Tumorigenesis
4. ALK Inhibitors in Monotherapy
4.1. The ALK Inhibitor Pioneer Crizotinib
- In a phase I clinical study of eleven refractory NBL patients, one patient obtained complete remission, and an additional three patients obtained stable disease. Of these patients, two had an R1275Q germline mutation, while the two somatic point mutations were R1275L and F1174L. The remaining seven patients, among them one harbouring the ALK R1275Q mutation, showed disease progression [32];
- In a follow-up phase II clinical study, twenty relapsed/refractory NBL cases (no germline mutations, no point mutation at F1245) were included, and only three patients showed complete or partial response. All of these patients, in addition to two with stable disease, harboured the ALK R1275Q mutation [44];
- A case report included two patients with ALK overexpression. It is not stated whether this overexpression resulted from ALK amplifications or increased mRNA expression. Both patients showed complete response, but one patient relapsed after 32 weeks of crizotinib monotherapy. The other patient remained in remission without further treatment during the two months of follow-up [52].
4.2. A Wide Selection of Second-Generation of ALK Inhibitors
4.2.1. TAE-684
4.2.2. Ceritinib/LDK-378
4.2.3. ASP3026
4.2.4. Brigatinib/AP26133
4.2.5. Ensartinib/X-396
4.2.6. AZD3463
4.2.7. CEP-37440
4.2.8. Alectinib/CH5424802
4.2.9. Belizatinib/TSR-011
4.2.10. Entrectinib/RDX-101
4.3. Third-Generation of ALK Inhibitors
4.3.1. Lorlatinib/PF-06463992
4.3.2. Repotrectinib/TPX-0005
4.4. Improved Targeting Effects: Types I ½ and II Kinase Inhibitors
4.5. Other Inhibitors
4.5.1. HSP90 Inhibition
4.5.2. Cell Differentiation by Retinoic Acids
5. Combination Therapy in NBL Treatment
5.1. Combinational Therapy with Pathway Inhibitors
5.1.1. Inhibitors of the PI3K-Akt-mTOR Pathway
5.1.2. Inhibitors of the RAS/MAPK Pathway
5.2. Combinatory Therapy with Other Agents
5.2.1. Inhibition of the Ubiquitin Kinase MDM2
5.2.2. Inhibition of Histone Deacytylases
5.2.3. Inhibition of Cyclin Dependant Kinases
5.2.4. Inhibition of the Axl Kinase
5.2.5. Inhibition of the Wnt/β-Catenin Pathway
5.3. On the Verge—The Combination of ALK Inhibitors with TRAIL
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Specific Positions | Residues |
---|---|
Auto-phosphorylation site | Y1278, Y1282, Y1283 |
NBL germline mutations | G1182, R1192, R1275 |
NBL hotspot mutations | F1174, F1245, R1275 |
Less common NBL mutations | I1170, I1171, Y1278 |
ALK gatekeeper mutation | L1196 |
Mutations involved in drug resistance | G1202, G1269 |
First-Generation Inhibitor | |||
Crizotinib Off-targets: ROS1, c-MET No CNS penetration Sensitive: R1275Q Resistant: F1174L/V | | ||
Second-Generation Inhibitors | |||
TAE-684 Sensitive: R1275Q, F1174L Discontinued | | Ceritinib Off-targets: IGFR1, ROS1 CNS penetration Resistant: F1174L/C | |
ASP3026 Off-targets: ROS1, ACK Resistant: L1196M | | Brigatinib Off-targets: ROS1, EGFR CNS penetration Sensitive: all NBL-associated point mutations | |
Ensartinib Sensitive: R1275Q, F1174L | | AZD3463 Off-target: IGFR1 Sensitive: NBL hotspot mutations | |
CEP-37440 Off-target: FAK CNS penetration Sensitive: NBL hotspot mutations | | Alectinib Sensitive: all NBL-associated point mutations, plus amplifications | |
Belizatinib Off-targets: IGFR1, JAK2, TrkA/B/C, c-Src CNS penetration Sensitive: R1275Q, L1196M | | Entrectinib Off-targets: ROS1, TrkA/B/C CNS penetration Sensitive: ALK amplifications | |
Third-Generation Inhibitors | |||
Lorlatinib Off-target: ROS1 CNS penetration Sensitive: NBL hotspot mutations | | Repotrectinib Off-targets: ROS1, TrkA/B/C CNS penetration Sensitive: all NBL-associated point mutations | |
Drug | Phase | Inclusion Criteria | Study Identifier | State | Published Data |
---|---|---|---|---|---|
Crizotinib | I/II | Refractory NBL | NCT00949770 | Completed | [32,44] |
I | Malignant neoplasms | NCT01121588 | Active | ||
III | High-risk NBL | NCT03126916 | Recruiting | ||
Ceritinib | I | ALK-activated tumours | NTC01742286 | Completed | [53] |
I | Relapsed/refractory NBL | NTC02780128 | Recruiting | ||
II | De novo NBL | NTC02559778 | Recruiting | ||
ASP3026 | I | Crizotinib-resistant tumours | NCT01284192 | Completed | [54] |
Ensartinib | II | Relapsed NBL | NTC03213652 | Recruiting | |
II | Relapsed/refractory NBL | NTC03155620 | Recruiting | ||
Entrectinib | I/II | ALK-activated tumours | NTC02650401 | Active | |
Lorlatinib | I | Relapsed/refractory NBL | NCT03107988 | Recruiting | |
I | De novo NBL | NCT04753658 | Recruiting |
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Brenner, A.K.; Gunnes, M.W. Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update. Pharmaceutics 2021, 13, 1427. https://doi.org/10.3390/pharmaceutics13091427
Brenner AK, Gunnes MW. Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update. Pharmaceutics. 2021; 13(9):1427. https://doi.org/10.3390/pharmaceutics13091427
Chicago/Turabian StyleBrenner, Annette K., and Maria W. Gunnes. 2021. "Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update" Pharmaceutics 13, no. 9: 1427. https://doi.org/10.3390/pharmaceutics13091427
APA StyleBrenner, A. K., & Gunnes, M. W. (2021). Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update. Pharmaceutics, 13(9), 1427. https://doi.org/10.3390/pharmaceutics13091427