Activation of cGAS-STING Pathway Is Associated with MSI-H Stage IV Colorectal Cancer

SIMPLE SUMMARY: Metastatic colorectal cancer is one of the most common causes of cancer-related mortality in adults. New therapeutic strategies are currently being implemented for the treatment of colorectal cancer which require new predictive markers. Metastatic colorectal cancer often presents microsatellite instability which is associated with a positive response to immune therapy. The findings of the present study demonstrate and discuss the DNA sensor cGAS and cyclic GMP–AMP receptor stimulator of interferon genes (STING) as potential new targets for novel therapeutic approaches based on immune checkpoint inhibitors in microsatellite unstable stage IV colorectal cancer. ABSTRACT: Colorectal cancer is the second most common cause of cancer-related mortality in adults. Understanding colorectal tumorigenesis at both the cellular and molecular levels is crucial for developing effective treatment options. Forty-one biopsy samples from patients with metastatic CRC (mCRC) were collected at Split University Hospital in Croatia. A total of 41 patients (21 with microsatellite unstable tumours and 20 with microsatellite stable tumours) were randomly included in the study. Immunolabelling of cGAS and STING in metastatic CRC was performed and further complemented by histological classification, tumour grade, and KRAS, NRAS, and BRAF mutational status of mCRC. In bivariate analysis, elevated expression of cGAS and STING was positively associated with MSI-H colon cancer (Fisher’s exact test, both p = 0.0203). Combined expression analysis of cGAS and STING showed a significantly higher percentage of patients with mCRC MSI-H with a fully or partially activated cGAS-STING signalling pathway (chi-square test, p = 0.0050). After adjusting for age, sex, and STING expression, increased cGAS expression remained significantly associated with MSI-H colon cancer in a multiple logistic regression model (β = 1.588, SE = ±0.799, p = 0.047). The cGAS-STING signalling axis represents a compelling new target for optimization of immune checkpoint inhibitor therapeutic approaches in patients with MSI-H stage IV CRC.