Inhibition of BAD-Ser99 phosphorylation synergizes with PARP inhibition to ablate PTEN-deficient endometrial carcinoma.
Cell Death Dis
; 13(6): 558, 2022 06 20.
Article
en En
| MEDLINE
| ID: mdl-35725817
ABSTRACT
Loss of phosphatase and tensin homolog (PTEN) impairs DNA double-strand repair and confers sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPis). However, PARPis also hyperactivate the MAPK and PI3K/AKT/mTOR pathways in PTEN-deficient endometrial carcinoma (EC), which allows the emergence of PARPi resistance. BCL-2-associated death promoter (BAD), integrates the common cell survival effects of the RAS/MEK/MAPK and PI3K/AKT/mTOR pathways. Herein, it was observed that increased BADSer99 (BADS99) phosphorylation in EC cells was significantly associated with PTEN-deficient status. Forced expression of phosphorylation deficient human BADS99A in PTEN-deficient EC cells significantly increased CASPASE 3/7 activity and decreased EC cell viability. Using NPB as a pharmacological inhibitor of pBADS99 phosphorylation, it was demonstrated that NPB synergized with PARPis (Olaparib, Rucaparib and Talazoparib) to enhance PARPi IC50 up to 60-fold and decreased survival, foci formation, and growth in 3D ex vivo culture of PTEN-deficient EC cells. Combined NPB-PARPi treatment of PTEN-deficient EC cells stimulated apoptosis and promoted DNA damage by impairment of homologous recombination. Using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonuclease system it was demonstrated that deletion of PTEN in PTEN replete EC cells enhanced the efficacy of combined NPB-PARPi treatment. Furthermore, combined inhibition of BADS99 phosphorylation and PARP ablated xenograft growth of PTEN-deficient EC cells. Similarly, a combination of NPB and PARPis significantly suppressed the growth of PTEN deficient patient-derived EC organoids. Hence, combined inhibition of BADS99 phosphorylation and PARP represents a rational and efficacious strategy to improve the prognosis of recurrent EC patients.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Endometriales
/
Inhibidores de Poli(ADP-Ribosa) Polimerasas
Límite:
Female
/
Humans
Idioma:
En
Revista:
Cell Death Dis
Año:
2022
Tipo del documento:
Article
País de afiliación:
China