Open AccessMET inhibition enhances PARP inhibitor efficacy in castration‐resistant prostate cancer by suppressing the ATM/ATR and PI3K/AKT pathways
Author(s) -
Zhou Sihai,
Dai Zhihong,
Wang Liang,
Gao Xiang,
Yang Liqin,
Wang Zhenwei,
Wang Qi,
Liu Zhiyu
Publication year - 2021
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.17037
Subject(s) - du145 , olaparib , cancer research , protein kinase b , pi3k/akt/mtor pathway , parp inhibitor , prostate cancer , crizotinib , poly adp ribose polymerase , chemistry , signal transduction , biology , cancer , medicine , microbiology and biotechnology , polymerase , lung cancer , lncap , biochemistry , enzyme , malignant pleural effusion , genetics
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.