Project Summary Disruption of the molecular circadian clock is indicative of poor prognosis in non-small cell lung cancers (NSCLCs), but direct evidence for a causal link between circadian clock deregulation and malignancy in human cancer is missing. We found that BMAL1 is downregulated in human NSCLCs, indicative of circadian disruption, low BMAL1 is an indicator of aggressive disease and poor prognosis. In addition, deletion of BMAL1 in a mouse model of NSCLC accelerates cancer progression. These data suggest that BMAL1, and by extension, circadian rhythms, exert a tumor-suppressive role in lung cancer. However, how BMAL1 restrains tumorigenesis and the mechanisms involved in suppression of BMAL1 remain unclear. A potential cause for BMAL1 suppression is the upregulation of MYC-family oncoproteins, which are amplified 50% of NSCLCs. We were the first to show that the molecular clock is disrupted by amplified MYC. In addition, our preliminary data suggest that, even in the presence of glucocorticoids, MYC suppresses BMAL1 expression in both NSCLC and normal lung epithelium, and thus disrupts circadian clock oscillation. To date, MYC amplification is the only identifiable cause of this circadian disruption in NSCLC. While CLOCK-BMAL1, and thus, oscillation of the molecular circadian clock, are necessary to maintain normal lung architecture and identity, we found that MYC activation led to loss of normal lung alveolar epithelial identity and induction of inappropriate proliferation. Notably, glucocorticoids have been shown to slow or halt the growth of some NSCLCs in preclinical and clinical studies, and our preliminary data suggest that glucocorticoids fail to suppress proliferation of lung cells when MYC is overexpressed. Taken together, we hypothesize that BMAL1 suppression and circadian disruption by MYC in NSCLC is critical for loss of alveolar cell identity, the emergence of malignancy, and resistance to glucocorticoids. To test this hypothesis, we propose two