UCSF

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease with recurrent driver mutations. Given the recent increase in targeted therapies, many of these are now considered "actionable" mutations, yet clinical trials continue to show limited improvements in patient overall survival. Thus, there is an urgent need to identify the key pathways and regulators underlying tumor progression and resistance. Here, we investigate the role of Notch3, a known regulator of epithelial lung development and previously implicated in tumor-propagation capacity, in the lung adenocarcinoma context. We demonstrate that, while Notch activity is not required for cell survival, Kras-mutant LUAD cells undergo epithelial-to-mesenchymal transitional state changes in response both direct and indirect mechanisms engaged by transcriptionally active Notch3. We use transcriptomic and epigenetic analyses to define a set of Notch3 target genes and utilize genome-wide screening approaches to show that a subset of these regulate Notch3-induced therapeutic resistance to covalent Kras(G12C) inhibition. Given recent clinical data from patients and preclinical in vitro models supporting a role for EMT in Kras(G12C) resistance, our datasets provide unique epigenetic and transcriptional resources to discover potential therapeutic targets for overcoming resistance and tumor progression.