Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 03, 2022
- Source ID
- 10.1038/s41467-022-28340-6
Entities
People
- Alex Vasquez
- Arkadiusz Gertych
- Avradip Chatterjee
- Beatrice S Knudsen
- Bo Zhou
- Chen Qian
- Dolores Di Vizio
- Edwin M Posadas
- Kavita Shah
- Leigh Ellis
- Michael R Freeman
- Mohini Kamra
- Natasha Kyprianou
- Ramachandran Murali
- Sungyong You
- Wei Yang
- Xiaopu Yuan
- Yeon-Joo Lee
- Yiwu Yan
Organizations
- National Cancer Institute
- United States Department of Defense