5/22/2023 0 Comments Ribosomal insidia bacteriaIn contrast, little is known about the molecular functions of RIPK2 in the metastasis of PC and other cancer types. RIPK2 is a Ser/Thr/Tyr kinase that has been well characterized in inflammation and innate immunity, functioning mainly via the NOD/RIPK2/NF-κB signaling pathway 10, 11. In the present study, through bioinformatic and functional analyses, we discover receptor-interacting protein kinase 2 (RIPK2) as one such particularly attractive target and show that RIPK2 is required for PC metastasis. Such targets have a high potential of rapid translation into the clinic to benefit at least a significant subset of PC patients. Candidate targets with the following characteristics are particularly attractive: (1) frequent overexpression in advanced PC, (2) significant association of high expression levels with poor prognosis, and (3) availability of potent and tolerable small-molecule inhibitors. Nevertheless, to further improve MFS-a strong surrogate of overall survival 9-novel therapeutic targets and their mechanisms of action in PC metastasis need to be identified. Longer follow-up studies showed that the drugs extended the median overall survival by 10–14 months 7, 8, unequivocally demonstrating that delaying PC metastasis provides strong clinical benefits. The approvals were based on phase III clinical trials using metastasis-free survival (MFS) as the primary endpoint for the first time 4, 5, 6. Food and Drug Administration (FDA) approved three androgen receptor (AR) inhibitors-apalutamide, enzalutamide, and darolutamide-for the treatment of non-metastatic castration-resistant PC (nmCRPC, also known as M0 CRPC). Despite advancements in PC treatment, distant metastasis continues to be a prominent cause of PC morbidity and mortality, inflicting considerable social and economic burdens 2, 3. Prostate cancer (PC) is the second most common non-skin cancer in men worldwide and causes about 360,000 deaths globally each year 1. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. 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. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Nature Communications volume 13, Article number: 669 ( 2022)ĭespite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
0 Comments
Leave a Reply. |