MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways.
J Cell Mol Med
; 25(24): 11157-11169, 2021 12.
Article
in En
| MEDLINE
| ID: mdl-34761497
ABSTRACT
Up to 30% of patients with metastatic castration-resistant prostate cancer (CRPC) patients carry altered DNA damage response genes, enabling the use of poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in advanced CRPC. The proto-oncogene mesenchymal-epithelial transition (MET) is crucial in the migration, proliferation, and invasion of tumour cells. Aberrant expression of MET and its ligand hepatocyte growth factor is associated with drug resistance in cancer therapy. Here, we found that MET was highly expressed in human CRPC tissues and overexpressed in DU145 and PC3 cells in a drug concentration-dependent manner and is closely related to sensitivity to PARP inhibitors. Combining the PARP inhibitor olaparib with the MET inhibitor crizotinib synergistically inhibited CRPC cell growth both in vivo and in vitro. Further analysis of the underlying molecular mechanism underlying the MET suppression-induced drug sensitivity revealed that olaparib and crizotinib could together downregulate the ATM/ATR signaling pathway, inducing apoptosis by inhibiting the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, enhancing the olaparib-induced antitumour effect in DU145 and PC3 cells. In conclusion, we demonstrated that MET inhibition enhances sensitivity of CRPC to PARP inhibitors by suppressing the ATM/ATR and PI3K/AKT pathways and provides a novel, targeted therapy regimen for CRPC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Phosphatidylinositol 3-Kinases
/
Proto-Oncogene Proteins c-met
/
Proto-Oncogene Proteins c-akt
/
Prostatic Neoplasms, Castration-Resistant
/
Ataxia Telangiectasia Mutated Proteins
/
Poly(ADP-ribose) Polymerase Inhibitors
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Cell Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2021
Document type:
Article
Affiliation country:
China