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Predicting Patient Outcomes with Gene-Expression Biomarkers from Colorectal Cancer Organoids and Cell Lines
Colorectal cancer is characterized by an extremely high mortality rate, mainly caused by the high metastatic potential of this type of cancer. To date, chemotherapy remains the backbone of the treatment of metastatic colorectal cancer. Three main chemotherapeutic drugs used for the treatment of metastatic colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan which is metabolized to an active compound SN-38. The main goal of this study was to find the genes connected to the resistance to the aforementioned drugs and to construct a predictive gene expression-based classifier to separate responders and non-responders. In this study we used 7 established colorectal cancer organoids to conduct correlational analysis of the expression and drug resistance. We also included in the study publicly available datasets of colorectal cancer cell lines, thus combining two different in vitro models relevant to cancer research. The obtained results demonstrated that the expression of just a small group of genes consistently correlates with resistance to standard chemotherapeutic drugs in different datasets. Some of these genes have been previously connected to prognosis or response to anticancer drugs, but some of them were linked to drug resistance for the first time. Constructed gene expression signatures based on some of these genes enable the stratification of Stage II/III and Stage IV colorectal cancer patients and can be further validated in the clinic to improve the results of the treatment. Thus, by leveraging both organoids and cell lines, our study demonstrates the power of combining diverse experimental systems to uncover new prognostic markers and deepen our understanding of drug resistance in cancer.