We propose that SCLC transformation from LUAD requires specific conditions in the background of p53/RB loss, including lack of both second site EGFR mutations and bypass pathway mutations that reactivate MAPK signaling and ETS TFs, and alterations in epigenetic modifiers such as CBP/p300 to reduce H3K27ac levels and alter chromatin accessibility, rendering gene expression suitable for NE differentiation. This evidence concerns the gene RB1 and small cell lung carcinoma.