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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting anaplastic lymphoma kinase (ALK) gene alterations in neuroblastoma by using alkylating pyrrole-imidazole
Yoko Ota1,2, Hiroyuki Yoda1,3, Takahiro Inoue2,3
1Division of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan.
Abstract:
Anaplastic lymphoma kinase (ALK) aberration is related to high-risk neuroblastomas and is an important therapeutic target. As acquired resistance to ALK tyrosine kinase inhibitors is inevitable, novel anti-ALK drug development is necessary in order to overcome potential drug resistance against ATP-competitive kinase inhibitors. In this study, to overcome ALK inhibitor resistance, we examined the growth inhibition effects of newly developed ALK-targeting pyrrole-imidazole polyamide CCC-003, which was designed to directly bind and alkylate DNA within the F1174L-mutated ALK gene. CCC-003 suppressed cell proliferation in ALK-mutated neuroblastoma cells. The expression of total and phosphorylated ALK was downregulated by CCC-003 treatment but not by treatment with a mismatch polyamide without any binding motif within the ALK gene region. CCC-003 preferentially bound to the DNA sequence with the F1174L mutation and significantly suppressed tumor progression in a human neuroblastoma xenograft mouse model. Our data suggest that the specific binding of CCC-003 to mutated DNA within the ALK gene exerts its anti-tumor activity through a mode of action that is distinct from those of other ALK inhibitors. In summary, our current study provides evidence for the potential of pyrrole-imidazole polyamide ALK inhibitor CCC-003 for the treatment of neuroblastoma thus offering a possible solution to the problem of tyrosine kinase inhibitor resistance.
Insights
A novel drug, CCC-003, targets anaplastic lymphoma kinase (ALK) gene mutations in neuroblastoma. This pyrrole-imidazole polyamide inhibits tumor growth by directly binding mutated ALK DNA, offering a new strategy against drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Anaplastic lymphoma kinase (ALK) aberrations are linked to high-risk neuroblastomas, making it a key therapeutic target.
- Acquired resistance to existing ALK tyrosine kinase inhibitors necessitates the development of novel drugs with distinct mechanisms of action.
Purpose of the Study:
- To investigate the efficacy of a new ALK-targeting pyrrole-imidazole polyamide, CCC-003, in overcoming resistance to ATP-competitive kinase inhibitors.
- To evaluate CCC-003's ability to suppress neuroblastoma cell proliferation and tumor progression.
Main Methods:
- Synthesized CCC-003, designed to bind and alkylate DNA within the F1174L-mutated ALK gene.
- Assessed CCC-003's effects on cell proliferation and ALK expression in neuroblastoma cell lines.
- Evaluated tumor progression in a human neuroblastoma xenograft mouse model.
Main Results:
- CCC-003 suppressed proliferation in ALK-mutated neuroblastoma cells.
- Treatment with CCC-003 downregulated total and phosphorylated ALK expression.
- CCC-003 demonstrated preferential binding to the F1174L mutation site and significantly inhibited tumor growth in vivo.
Conclusions:
- CCC-003 exhibits anti-tumor activity through a unique mechanism involving direct DNA binding to mutated ALK.
- This novel pyrrole-imidazole polyamide shows potential as a therapeutic agent for neuroblastoma, addressing challenges posed by tyrosine kinase inhibitor resistance.
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