MET inhibition enhances PARP inhibitor efficacy in castration‐resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways

• Published in: Journal of cellular and molecular medicine 2021-12, Vol.25 (24), p.11157-11169
• Main Authors: Zhou, Sihai, Dai, Zhihong, Wang, Liang, Gao, Xiang, Yang, Liqin, Wang, Zhenwei, Wang, Qi, Liu, Zhiyu
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenosine; AKT protein; Androgens; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM/ATR pathway; c-Met protein; Cancer therapies; Castration; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; CRPC; Disease Models, Animal; DNA damage; DNA damage response; Drug resistance; Drug Synergism; Gene Silencing; Genes; Hepatocyte growth factor; Humans; Kinases; Male; Medical research; Membranes; Mesenchyme; MET inhibitor; Metastases; Mice; Mutation; Original; PARP inhibitor; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT pathway; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - etiology; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Ribose; Signal transduction; Signal Transduction - drug effects; Targeted cancer therapy; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.17037

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.