Prediction of Tubulin Inhibitor Sensitivity in Colon Cancer

Abstract

Colorectal cancer is the second most common cause of cancer death worldwide. Despite advances in molecular strategies for stratifying patients with colorectal cancer, their clinical implementation remains limited. Previous efforts have mainly focused on the development of prognostic gene expression signatures; however predictive biomarkers remain essential for translating molecular insights into effective therapies and ultimately enhancing patient outcomes. This study advances the translation of a molecular signature identified in colon cancer toward new therapeutic options for clinical applications. We leveraged public gene expression datasets to develop a prognostic 37-gene signature in colon cancer and validated its prognostic value across six clinical cohorts. We subsequently investigated the biological processes associated with the signature and its predictive potential for therapeutic response. We further evaluated its predictive capability for tubulin inhibitor response using paclitaxel in vitro and in vivo in patient-derived preclinical models. The signature showed prognostic performance comparable to published gene expression signatures across six independent cohorts without clinical covariates. The signature was associated with the mitotic phase of the cell cycle and identified a population of patient-derived colon cancer models sensitive to tubulin inhibitor drugs, subsequently referred to as the Colon Tubulin-Inhibitor Expression Signature (ColoTubIn). Low ColoTubIn scores were associated with increased paclitaxel sensitivity. Hence, ColoTubIn performs comparably to existing prognostic signatures while additionally identifying a molecularly defined subgroup of colon cancers with therapeutic potential. ColoTubIn is of particular interest since it can serve as a basis for drug repurposing strategies leveraging existing safety data to accelerate translation into the clinic.