RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer

Abstract

Background: Colorectal cancer is one of the primary causes of cancer-related deaths and 5-fluorouracil (5-FU) therapy remains the cornerstone of treatment in these patients. Resistance to 5-FU represents a major obstacle; therefore, finding new predictive and prognostic markers is crucial for improvement of patient outcomes. Recently a new type of programmed cell death was discovered—necroptosis, which depends on receptor interacting protein 3 (RIPK3). Preclinical data showed that necroptotic cell death is an important effector mechanism of 5-FU-mediated anticancer activity.
 
 Purpose: To investigate the predictive and prognostic performance of RIPK3 expression in primary tumors. Methods: Colon cancer patients (n=74) with metastatic stage were included in this retrospective study and all were treated with first-line 5-FU based chemotherapy. Immunohistochemical staining was performed.
 
 Results: The progression free survival for the low expression group of RIPK3 was 5.6 months (95% CI, 4.4-6.8) vs 8.4 months (95% CI, 6.4-10.3) of the group with high expression (p=0.02). Moreover, patients with high expression of RIPK3 were associated with lower risk of disease progression HR 0.61 (95% CI, 0.38-0.97; p=0.044). Patients with high expression levels of RIPK3 also had significantly longer mean overall survival (OS) of 29.3 months (95% CI, 20.8-37.8) as compared with those with low expression: 18.5 months (95% CI, 15.06-21.9) (p= 0.036). In addition, univariate analysis showed that high level of RIPK3 expression was associated with a longer OS HR 0.59 (95% CI, 0.35-0.98; p=0.044).
 
 Conclusions: This study suggests that expression of RIPK3 in primary tumors of metastatic colon cancer patients should be further investigated for its potential as a promising predictive and prognostic marker.

Current translational potential and underlying molecular mechanisms of necroptosis

“…Briefly, both pro- and anti-tumoral effects have been demonstrated following necroptosis in cancer development and progression. The anti-tumoral effect of necroptosis has been shown in many types of cancer in which the expression of RIPK3 66,67 or MLKL 68 was silenced or polymorphisms in their coding genes lead to modified expression of necrosomal components 66,69 . In general, necroptosis resistance of cancer cells is a common process, and escape from necroptosis was suggested to be a potential hallmark of cancer, similar to the escape from apoptosis 64 .…”

Autoantibody landscape of advanced prostate cancer

“…SART3 has been shown to induce both a humoral and cellular adaptive immune response in a vaccination study of patients with advanced colorectal cancer 67 . RIPK3 is a tumor suppressor whose downregulation has been associated with tumorigenesis, immunomodulation, and poor clinical prognosis in colorectal cancer 68,69 , although its exact role in the adaptive immunity is still under investigation. While confirmatory studies are needed, the present study in conjunction with supporting studies in other cancer types nominates potential immune biomarkers and therapeutic targets in mCRPC.…”

Necroptosis in Immuno-Oncology and Cancer Immunotherapy

“…Overall, the relationship of pro-necroptotic molecules' gene-expression with cancer patient's prognosis seems to be highly context-dependent. For example, the analysis of RIPK3 expression in 74 primary CRC tumors treated with first-line 5-fluorouracil (5-FU) chemotherapy revealed that high expression levels of RIPK3 correlated with a significantly longer overall survival and lower risk of disease progression in CRC patients [208]. Consistent with this, low expression of RIPK1 was correlated with, higher tumor progression in head and neck squamous cell carcinoma (HNSCC) patients [209] and worse prognosis in human hepatocellular carcinoma (HCC) patients [210].…”

“…Longer mean overall survival after treatment with 5-fluorouracil (5-FU) [208] Low expression Breast cancer Worse prognosis [201] Colon rectal cancer (CRC) Worse overall survival and disease-free interval. [202] RIPK1 expression…”