Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome.
Drug Resist Updat
; 74: 101081, 2024 May.
Article
em En
| MEDLINE
| ID: mdl-38521003
ABSTRACT
Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent EML4-ALK variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that Eml4-Alk variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients. ONE SENTENCE SUMMARY:
Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Pulmao
Base de dados:
MEDLINE
Assunto principal:
Compostos Organofosforados
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Quinases da Família src
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Resistencia a Medicamentos Antineoplásicos
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Proteoma
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Inibidores de Proteínas Quinases
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Quinase do Linfoma Anaplásico
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Neoplasias Pulmonares
Limite:
Animals
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Humans
Idioma:
En
Revista:
Drug Resist Updat
/
Drug resist. updat
/
Drug resistance updates
Assunto da revista:
ANTINEOPLASICOS
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Alemanha