Targeting BET Bromodomains in Recalcitrant Cancers

Clift, Sheena, Biochemistry and Molecular Genetics - Graduate School of Arts and Sciences, University of Virginia
Mayo, Marty, Department of Biochemistry and Molecular Genetics, University of Virginia

Pancreatic and lung cancers have some of the worst five-year survival rates of all malignancies. These aggressive cancers are often diagnosed as metastatic disease and are refractory to therapeutic interventions. Driving mutations in these diseases are often therapeutic targets, but cancer cells evade death by circumventing the pathways targeted by drugs. In order to do this, tumor cells will often undergo transcriptional reprogramming events, such as epithelial-to-mesenchymal transition (EMT). Transcriptional reprogramming relies heavily on epigenetic reprogramming to define active enhancers and promoters for transcriptional activation. Bromodomain extraterminal domain (BET) proteins associate with enhancers and promoters to coordinate transcriptional activation of genes. We hypothesized that inhibition of BET proteins will disrupt the transcriptional reprogramming associated with EMT and drug resistance in cancer. In combination with targeted therapy against the mitogen-activated protein kinase (MAPK) pathway, BET inhibition results in increased apoptosis and decreased expression of genes associated with EMT and stemness in pancreatic cancer cell cultures. Based on histological analysis of an in vivo xenograft model of pancreatic cancer, we show that combined MAPK pathway and BET inhibition is more effective in inducing tumor regression than MAPK pathway inhibition alone. In an EMT model of lung cancer, BET inhibition markedly decreased the ability of cells to migrate and invade. In this dissertation, I present evidence of the therapeutic value of using BET inhibitors to treat pancreatic and lung adenocarcinomas.

PHD (Doctor of Philosophy)
pancreatic cancer, lung cancer, BRD4, targeted therapy, trametinib, I-BET151, JQ1, transcription
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