Cellular Origins of EGFR-driven Lung Cancer Cells Determines Sensitivity to Therapy

The purpose of this research is to study the cellular origins of EGFR-mutant lung cancers and their responses to therapies. We discovered that activation of EGFR T790M/L858R mutation in lung epithelial cells can drive lung cancers with alveolar or bronchiolar features, which can be originated from alveolar type 2 (AT2) cells or bronchioalveolar stem cells (BASCs), but not basal cells or club cells of the trachea. Crucially, the tumoroids with different cell-of-origins or epigenetic states had distinct drug vulnerabilities. Overall design: RNA-sequencing profiles of murine lung organoids with or without EGFR T790M/L858R mutations before ex vivo transplantation, and EGFR T790M/L858R tumor organoids after ex vivo transplantation.