Acetylation of NFkB in NSCLC resistance models
Abstracts
Initial Award Abstract |
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Lung cancer is the leading cause of cancer death in the United States. Tobacco smokers have the greatest risk of lung cancer and account for 80-90% of these deaths. Current treatment options for patients with EGFR mutant lung adenocarcinomas include highly effective EGFR tyrosine kinase inhibitors (TKIs). However, while these targeted therapies initially elicit robust tumor responses, invariably tumor progression occurs due to incomplete responses leaving residual resistance cell populations, which is mediated by activation of the transcription factor NFkB. Here, I identify a role for NFkB acetylation in lung cancer and present a potential novel strategy of combination-based drug therapy of EGFR and BET inhibitors, which block BRD4 from interacting with acetylated lysine targets, to circumvent acquired resistance in mutant EGFR lung adenocarcinomas. This is particularly exciting as BET inhibitors are currently underway in human clinical trials.
Our preliminary studies have shown that BRD4 is a co-activator of NFkB driven pro-survival genes in response to EGFR inhibitors. Additionally, we can completely disrupt the interaction between RelA, the transactivation subunit of NFkB, and BRD4 either using chemical inhibitors, such as the BET bromodomain inhibitor JQ1, or with our acetyl-lysine mutant (RelA-K310R) which mimics the unacetylated state of the protein. This proposal aims to define the role of RelA-K310ac in resistance models of NSCLC and test combination-based drug therapy of EGFR TKIs and BET inhibitors to evade acquired resistance. Ultimately these studies will contribute to our overall understanding of mechanisms promoting resistance to targeted therapies in lung cancer and elucidate combinatorial therapeutic strategies that would prolong patient response to targeted therapies. |
