Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities.
Cell Rep
; 14(5): 979-990, 2016 Feb 09.
Article
en En
| MEDLINE
| ID: mdl-26804906
Due to loss of p16ink4a in pancreatic ductal adenocarcinoma (PDA), pharmacological suppression of CDK4/6 could represent a potent target for treatment. In PDA models, CDK4/6 inhibition had a variable effect on cell cycle but yielded accumulation of ATP and mitochondria. Pharmacological CDK4/6 inhibitors induce cyclin D1 protein levels; however, RB activation was required and sufficient for mitochondrial accumulation. CDK4/6 inhibition stimulated glycolytic and oxidative metabolism and was associated with an increase in mTORC1 activity. MTOR and MEK inhibitors potently cooperate with CDK4/6 inhibition in eliciting cell-cycle exit. However, MTOR inhibition fully suppressed metabolism and yielded apoptosis and suppression of tumor growth in xenograft models. The metabolic state mediated by CDK4/6 inhibition increases mitochondrial number and reactive oxygen species (ROS). Concordantly, the suppression of ROS scavenging or BCL2 antagonists cooperated with CDK4/6 inhibition. Together, these data define the impact of therapeutics on PDA metabolism and provide strategies for converting cytostatic response to tumor cell killing.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Quinasa 4 Dependiente de la Ciclina
/
Quinasa 6 Dependiente de la Ciclina
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Cell Rep
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos