Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases.
Nat Med
; 22(7): 723-6, 2016 07.
Article
en En
| MEDLINE
| ID: mdl-27270588
ABSTRACT
Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Encefálicas
/
Neoplasias de la Mama
/
Morfolinas
/
Apoptosis
/
Complejos Multiproteicos
/
Serina-Treonina Quinasas TOR
/
Everolimus
/
Inhibidores de las Quinasa Fosfoinosítidos-3
/
Aminopiridinas
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Nat Med
Asunto de la revista:
BIOLOGIA MOLECULAR
/
MEDICINA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos