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Ref Type | Journal Article | ||||||||||||
PMID | (34591871) | ||||||||||||
Authors | Ota Y, Yoda H, Inoue T, Watanabe T, Shinozaki Y, Takatori A, Nagase H | ||||||||||||
Title | Targeting anaplastic lymphoma kinase (ALK) gene alterations in neuroblastoma by using alkylating pyrrole-imidazole polyamides. | ||||||||||||
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Abstract Text | 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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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CCC-003 | CCC 003|CCC003 | ALK Inhibitor 33 | CCC-003 is a pyrrole-imidazole polyamide that inhibits ALK, potentially leading to decreased tumor cell proliferation and reduced growth of ALK-mutant tumors (PMID: 34591871). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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ALK F1174L | neuroblastoma | sensitive | CCC-003 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, CCC-003 treatment resulted in decreased cell proliferation and induction of apoptosis in neuroblastoma cell lines harboring ALK F1174L in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 34591871). | 34591871 |
ALK F1174L | Advanced Solid Tumor | sensitive | CCC-003 | Preclinical - Cell culture | Actionable | In a preclinical study, CCC-003 inhibited viability in transformed cells expressing ALK F1174L in culture (PMID: 34591871). | 34591871 |