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 Vizio, Edwin M. Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Kavita Shah, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R. Freeman and Wei Yang ()
Additional contact information
Yiwu Yan: Cedars-Sinai Medical Center
Bo Zhou: Cedars-Sinai Medical Center
Chen Qian: Cedars-Sinai Medical Center
Alex Vasquez: Cedars-Sinai Medical Center
Mohini Kamra: Purdue University
Avradip Chatterjee: Cedars-Sinai Medical Center
Yeon-Joo Lee: Cedars-Sinai Medical Center
Xiaopu Yuan: Cedars-Sinai Medical Center
Leigh Ellis: Cedars-Sinai Medical Center
Dolores Vizio: Cedars-Sinai Medical Center
Edwin M. Posadas: Cedars-Sinai Medical Center
Natasha Kyprianou: Department of Urology, Icahn School of Medicine at Mount Sinai, New York
Beatrice S. Knudsen: Cedars-Sinai Medical Center
Kavita Shah: Purdue University
Ramachandran Murali: Cedars-Sinai Medical Center
Arkadiusz Gertych: Cedars-Sinai Medical Center
Sungyong You: Cedars-Sinai Medical Center
Michael R. Freeman: Cedars-Sinai Medical Center
Wei Yang: Cedars-Sinai Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28340-6

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