Circadian rhythm disruption in LKB1-mutant lung adenocarcinoma Restricted; Files & ToC

Abstract

Mutations in LKB1 are a common occurrence in KRAS-mutant LUAD and ultimately result in an aggressive disease that is resistant to current therapies, including immunotherapy. LKB1 has many possible connections to regulation of the circadian clock, and the circadian clock has many important connections to regulation of cancer-relevant pathways. This work investigates how loss of LKB1 alters expression of clock-related genes and proteins. We find that expression of PER1, at both the transcript and protein level, is increased in LKB1-mutant LUAD, and that this high PER1 expression contributes to invasion and proliferation of cells lacking LKB1, suggesting a context-specific oncogenic role of PER1. We also report that high PER1 expression is associated with low expression of PD-L1, a biomarker of immunotherapy resistance. Further experiments found that LKB1 loss alters rhythmic gene expression, with LKB1-knockout cells having fewer and different oscillating genes and less rhythmic expression of BMAL1. We also investigated the molecular mechanism by which LKB1 regulates the circadian clock. Finally, we investigated whether we could inhibit BMAL1 activity and inhibit growth of LKB1-mutant tumors in vivo. We found that CLK8, reported as an inhibitor of CLOCK nuclear localization, was relatively well tolerated at doses of up to 25 mg/kg and that treatment with this higher dose of CLK8 modestly inhibited growth of A549 xenograft tumors. Further mechanistic studies were inconclusive as to whether CLK8’s effect on tumor growth was due to its published mechanism, but BMAL1-luciferase reporter assays in A549 and GEMM-derived cells confirmed that CLK8 treatment decreased BMAL1 expression. Future studies should further explore the mechanism by which LKB1 regulates the circadian clock.

Table of Contents

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About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Molecular Biology, Cell
Keyword	BMAL1 STK11 lung cancer PER1 LKB1 cancer biology lung adenocarcinoma tumor supppressor circadian rhythm
Committee Chair / Thesis Advisor	Melissa Gilbert-Ross, Emory University
Committee Members	Shirley Zhang, Emory University Wei Zhou, Emory University Yong Wan, Emory University Sumin Kang, Emory University

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