The paper introduces GENEVA, a scalable single-cell resolution platform designed to improve the accuracy of preclinical cancer drug testing. By creating mosaic tumor models that blend diverse patient-derived and cancer cell lines into single experiments, the platform captures how different genetic backgrounds respond to treatments simultaneously. Applying this technology to KRAS-G12C inhibitors, researchers discovered that mitochondrial hyperactivation drives cell death while epithelial-to-mesenchymal transition acts as a specific resistance mechanism in living models. These high-resolution insights allowed for the identification of novel drug combinations, such as pairing KRAS inhibitors with mTOR or TGFβ/EMT blockers, to enhance therapeutic efficacy. Ultimately, the framework aims to bridge the gap between initial laboratory findings and actual patient outcomes by accounting for the inherent complexity of human tumors.

References:

• Yu J X, Suh J M, Popova K D, et al. The GENEVA platform models tumor mosaicism to reveal variations of responses to KRAS inhibitors and identify improved drug combinations[J]. Nature Cancer, 2026: 1-16.