Resumen
Today, clinical management for the majority of cancer patients is still based on a ?one-size-fits-all? approach. To improve the outcomes in the era of personalized medicine, it is essential to stratify patients based on established and novel biomarkers. In the present study, we investigated a SMAD4 loss-of-function mutation, which is associated with chemoresistance and decreased overall survival in colorectal cancer (CRC). To investigate the molecular mechanism behind the impact on drug response, we used CRISPR technology on patient-derived organoid models (PDOs) of CRC. We showed that PDOs with loss-of-function SMAD4 mutations are sensitive to MEK-inhibitors. Using a novel four-gene signature reliably predicts sensitivity towards MEK-inhibitors, regardless of the RAS and BRAF status. The present study is a significant step towards personalized cancer therapy by identifying a new biomarker.