Monitoring melanoma patients on treatment reveals a distinct macrophage population driving targeted therapy resistance.
Cell Rep Med
; 5(7): 101611, 2024 Jul 16.
Article
em En
| MEDLINE
| ID: mdl-38942020
ABSTRACT
Resistance to targeted therapy remains a major clinical challenge in melanoma. To uncover resistance mechanisms, we perform single-cell RNA sequencing on fine-needle aspirates from resistant and responding tumors of patients undergoing BRAFi/MEKi treatment. Among the genes most prominently expressed in resistant tumors is POSTN, predicted to signal to a macrophage population associated with targeted therapy resistance (TTR). Accordingly, tumors from patients with fast disease progression after therapy exhibit high POSTN expression levels and high numbers of TTR macrophages. POSTN polarizes human macrophages toward a TTR phenotype and promotes resistance to targeted therapy in a melanoma mouse model, which is associated with a phenotype change in intratumoral macrophages. Finally, polarized TTR macrophages directly protect human melanoma cells from MEKi-induced killing via CD44 receptor expression on melanoma cells. Thus, interfering with the protective activity of TTR macrophages may offer a strategy to overcome resistance to targeted therapy in melanoma.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
/
Macrófagos
/
Melanoma
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Rep Med
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Suíça