NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.
Commun Biol
; 3(1): 776, 2020 12 16.
Article
em En
| MEDLINE
| ID: mdl-33328556
ABSTRACT
Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
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Receptor trkA
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Inibidores de Proteínas Quinases
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Domínios e Motivos de Interação entre Proteínas
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Mutação
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Neoplasias
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Commun Biol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos