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

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.

Cancer Cells Haploinsufficient for ATM Are Sensitized to PARP Inhibitors by MET Inhibition

“…This agrees also with the recent report that increased MET protein expression was found in primary cultures of PARPi resistant high-grade serous ovarian carcinomas [ 41 ]. Again, in line with data reported here, it has been recently shown that in cellular models of castration-resistant prostate cancer, MET inhibition enhances the efficacy of PARPi by suppressing the ATM /ATR and PI3K/AKT pathways [ 42 ].…”

Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer

“…MCPH1 recruits ATM and NBN to DNA damage repair foci as part of the early DNA damage response [ 50 ]. The functional loss of ATM or NBN, two genes that are downregulated in our study, is associated with poor survival in PCa patients [ 50 , 51 , 52 ] and sensitizes PARP inhibitor therapies. Androgen receptor splice variant expression, in contrast, appears to reactivate DNA damage repair gene expression previously thwarted by ADT.…”

Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging

“…The biological importance of this is underscored by our finding that three differentially drug-responsive motility phenotypes co-occur in parallel in drug-resistant PC3M-D R cells, including a non-elongated shape, yet highly motile phenotype. Notably, Met levels and signalling are upregulated in advanced prostate cancer patients, associated with Olaparib-resistance in prostate cells and regulate invasion in vitro and tumourigenesis in vivo 55 , suggesting that such phenotype plasticity might be a general feature of drug-resistant cells.…”