Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis

Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Mohini Kamra, Avradip Chatterjee, Yeon Joo Lee, Xiaopu Yuan, Leigh Ellis, Dolores Di Vizio, Edwin M. Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Kavita Shah, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R. Freeman, Wei Yang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.

Original languageEnglish
Article number669
JournalNature Communications
Issue number1
StatePublished - Dec 2022


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