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

• Published in: Nature communications 2022-02, Vol.13 (1), p.669-17, Article 669
• Main Authors: Yan, Yiwu, Zhou, Bo, Qian, Chen, Vasquez, Alex, Kamra, Mohini, Chatterjee, Avradip, Lee, Yeon-Joo, Yuan, Xiaopu, Ellis, Leigh, Di Vizio, Dolores, Posadas, Edwin M., Kyprianou, Natasha, Knudsen, Beatrice S., Shah, Kavita, Murali, Ramachandran, Gertych, Arkadiusz, You, Sungyong, Freeman, Michael R., Yang, Wei
• Format: Article
• Language: English
• Subjects: 13/51; 14/105; 14/5; 38/70; 631/45/475; 631/67/322; 631/67/589/466; 82/1; 82/16; 82/29; 82/58; 96/109; 96/31; 96/34; 96/35; 96/44; 96/63; Animals; c-Myc protein; Castration; Cell Line, Tumor; Cell Proliferation - genetics; Drug development; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; HEK293 Cells; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; Kaplan-Meier Estimate; Kinases; Male; MAP kinase; Medical prognosis; Metastases; Metastasis; Mice; Mice, SCID; Morbidity; Mortality; multidisciplinary; Myc protein; Neoplasm Metastasis; Patients; PC-3 Cells; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein kinase; Protein Kinase Inhibitors - pharmacology; Protein Stability; Proteins; Proteomics; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyridazines - pharmacology; Receptor-Interacting Protein Serine-Threonine Kinase 2 - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinase 2 - genetics; Receptor-Interacting Protein Serine-Threonine Kinase 2 - metabolism; Receptors; Science; Science (multidisciplinary); Stability analysis; Therapeutic targets; Xenograft Model Antitumor Assays - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28340-6

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. Distant metastasis is a major reason for mortality in patients with prostate cancer (PC). Here, the authors show that receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and its targeting impairs PC metastasis development.