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MET inhibition enhances PARP inhibitor efficacy in castration-resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways |
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| Authors: | Sihai Zhou Zhihong Dai Liang Wang Xiang Gao Liqin Yang Zhenwei Wang Qi Wang Zhiyu Liu |
| Institution: | 1. Department of Urology, The Second Affiliated Hospital of Dalian Medical University, DaLian, China
Contribution: Data curation (lead), Formal analysis (lead), ?Investigation (lead), Methodology (lead), Writing - original draft (lead), Writing - review & editing (lead);2. Department of Urology, The Second Affiliated Hospital of Dalian Medical University, DaLian, China Contribution: Data curation (equal), Formal analysis (equal), Methodology (equal), Writing - original draft (equal), Writing - review & editing (equal);3. Department of Urology, The Second Affiliated Hospital of Dalian Medical University, DaLian, China Contribution: Data curation (equal), Formal analysis (equal), ?Investigation (equal), Methodology (equal), Writing - original draft (equal), Writing - review & editing (equal);4. Department of Urology, The Second Affiliated Hospital of Dalian Medical University, DaLian, China Contribution: Data curation (equal), ?Investigation (equal), Writing - original draft (equal);5. Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, China Contribution: Data curation (equal), Formal analysis (equal), ?Investigation (equal), Methodology (equal);6. Department of Respiratory Medicine, The Second Affiliated Hospital of Dalian Medical University, DaLian, China;7. Department of Urology, The Second Affiliated Hospital of Dalian Medical University, DaLian, China |
| 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. |
| Keywords: | ATM/ATR pathway CRPC DNA damage response MET inhibitor PARP inhibitor PI3K/AKT pathway |