CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.
Cancer Cell
; 26(1): 136-49, 2014 Jul 14.
Article
en En
| MEDLINE
| ID: mdl-25002028
ABSTRACT
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Quinasa 4 Dependiente de la Ciclina
/
Quinasa 6 Dependiente de la Ciclina
/
Inhibidores de las Quinasa Fosfoinosítidos-3
/
Mutación
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos