# Disruption of the circadian clock in lung cancer

> **NIH CA R01** · UNIVERSITY OF ROCHESTER · 2026 · $428,791

## Abstract

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 

## Key facts

- **NIH application ID:** 11304496
- **Project number:** 5R01CA282225-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Brian James Altman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $428,791
- **Award type:** 5
- **Project period:** 2024-04-01T00:00:00 → 2029-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11304496

## Citation

> US National Institutes of Health, RePORTER application 11304496, Disruption of the circadian clock in lung cancer (5R01CA282225-03). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/11304496. Licensed CC0.

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