Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	16	9	2021	e0257718	PLoS One

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CCC-003	CCC-003	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CCC-003		CCC 003\|CCC003	ALK Inhibitor 32	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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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