Phenotype-dependent subtyping exposes high MYC activity as a targetable dependency in LuAd

Although 30-40% of human Non-Small Cell lung cancers show low level amplification of c-MYC and genetic evidence supports c-Myc as a key downstream effector of KRas-driven tumourigenesis in mouse models, the functional contribution of MYC to human lung cancer remains unclear. We applied a phenotype-based classifier to the TCGA Lung Adenocarcinoma (LuAd) cohort and found that high MYC transcriptional activity identifies a subset of LuAd with significantly reduced survival. Application of the same methodology to a panel of genetically engineered mouse models identified multiple genotypes that yield the high MYC activity phenotype, disease positioning such models as reflective of distinct subsets of human LuAd. We show that high MYC activity predicts sensitivity to a small molecule dual-inhibitor of the MYC…