Predicting patient outcomes with gene-expression biomarkers from colorectal cancer organoids and cell lines.

Abstract

Introduction: Colorectal cancer (CRC) 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.

Methods: In this study, we analyzed gene expression profiles of seven patient-derived CRC organoids and performed correlation analyses between gene expression and IC50 values for the three standard-of-care chemotherapeutic drugs. 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. Logistic regression was used to build gene expression-based classifiers for metastatic Stage IV and non-metastatic Stage II/III CRC patients. Prognostic performance was evaluated through Kaplan-Meier survival analysis and log-rank tests, while independent prognostic significance was assessed using multivariate Cox proportional hazards modeling.

Results: A small set of genes showed consistent correlation with resistance to chemotherapy across different datasets. While some genes were previously implicated in cancer prognosis and drug response, several were linked to drug resistance for the first time. The resulting gene expression signatures successfully stratified Stage II/III and Stage IV CRC patients, with potential clinical utility for improving treatment outcomes after further validation.

Discussion: This study highlights the advantages of integrating diverse experimental models, such as organoids and cell lines, to identify novel prognostic biomarkers and enhance the understanding of chemotherapy resistance in CRC.