Identification of treatment‐induced vulnerabilities in pancreatic cancer patients using functional model systems

Despite the advance and success of precision oncology in gastrointestinal cancers, the frequency of molecular‐informed therapy decisions in pancreatic ductal adenocarcinoma (PDAC) is currently neglectable. We present a longitudinal precision oncology platform based on functional model systems, including patient‐derived organoids, to identify chemotherapy‐induced vulnerabilities. We demonstrate that treatment‐induced tumor cell plasticity in vivo distinctly changes responsiveness to targeted therapies, without the presence of a selectable genetic marker, indicating that tumor cell plasticity can be functionalized. By adding a mechanistic layer to precision oncology, adaptive processes of tumors under therapy can be exploited, particularly in highly plastic tumors, such as pancreatic cancer.