CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress.
Mol Cell
; 80(3): 410-422.e6, 2020 11 05.
Article
en En
| MEDLINE
| ID: mdl-33108758
ABSTRACT
While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Pirazinas
/
Pirazoles
/
Péptidos y Proteínas de Señalización Intracelular
/
Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos