Histological transformation from adenocarcinoma to small-cell carcinoma frequently occurs in castration-resistant prostate cancers and epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas (LUADs). Specifically, EGFR-mutant LUADs with bi-allelic inactivation of both RB1 and TP53 have a high risk of small-cell transformation after acquiring resistance to EGFR tyrosine kinase inhibitor. These transformed small-cell lung cancers (T-SCLCs) are highly aggressive tumours with a poor prognosis. Given that oncogene-driven LUAD originates from alveolar type II (AT2) cells and SCLC arises from pulmonary neuroendocrine cells (PNECs), the mechanisms that drive this cell-type transition have remained unknown.

To investigate the stepwise transformation of EGFR-mutant LUAD to SCLC, Gardner and colleagues manipulated specific genes in AT2 cells or PNECs by developing a promoter-restricted adenoviral ERPMT (oncogenic Egfr, Rb1fl/fl, Trp53fl/fl, Myc, rtTA3) genetically engineered mouse model. This induced a phenotype similar to the histological transformation observed in humans. The authors initially induced LUAD through mutational activation of EGFR in AT2 cells and subsequently transformed those tumours into SCLCs by inhibiting mutant EGFR and introducing alterations in oncogenic drivers.