Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor.
Cancer Cell
; 39(10): 1404-1421.e11, 2021 10 11.
Article
en En
| MEDLINE
| ID: mdl-34520734
ABSTRACT
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2- breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Ciclo Celular
/
Quinasa 2 Dependiente de la Ciclina
/
Quinasa 4 Dependiente de la Ciclina
/
Quinasa 6 Dependiente de la Ciclina
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cancer Cell
Asunto de la revista:
NEOPLASIAS
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos