RON receptor tyrosine kinase regulates abiraterone resistance in prostate cancer via the methylation-dependent and independent dual functions of DNMT1.

Acquired resistance to the CYP17 inhibitor abiraterone is a critical challenge in the clinical treatment of metastatic prostate cancer; however, the mechanisms driving this resistance remain elusive. This study suggests that aberrant RON expression plays an important role in the development of acquired abiraterone resistance in prostate cancer cells. Increased RON expression was observed in most clinical tumor samples with an abiraterone-insensitive phenotype. In established prostate cancer cell lines, aberrant RON expression is associated with increased abiraterone resistance and enhanced migratory activity. These effects are mediated through dual regulatory functions of DNA methyltransferase 1(DNMT1): RON-mediated regulation of the canonical methyltransferase activity of DNMT1, which inhibits receptor-interacting protein kinase 3(RIPK3) expression, leading to increased cellular survival with impaired RIPK3/MLKL-involved cell death signaling. Concurrently, RON-driven non-methyltransferase activity of DNMT1 is associated with altered mitochondrial functions, thereby potentially enhancing cellular migration. The multi-kinase inhibitor BMS-777607, which has activity against RON, in combination with abiraterone suppressed both proliferation and metastasis in abiraterone-resistant xenograft tumors. The discovery of the RON-DNMT1-RIPK3 functional axis and the association between RON-DNMT1 and mitochondrial bioenergetic activity in this work strongly suggest RON as a critical driver of abiraterone resistance and a potential therapeutic target in prostate cancer.