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UBC Theses and Dissertations

Resistance to BET inhibitors in lung adenocarcinoma is mediated through casein kinase 2 phosphorylation of BRD4 Calder, Jack


Lung cancer is the leading cause of cancer related death in both men and women worldwide, mainly due to the lack of effective therapies. The development of specific chemical compounds that target epigenetic post-translational modifications has recently emerged as an excellent approach for validating new treatment strategies for diseases that have complex underlying mechanisms. JQ1 is a small-molecule inhibitor of the bromodomain and extraterminal (BET) family proteins, which function as important reader molecules of acetylated histones and recruit transcriptional activators to specific promoter sites. In many cancer lines the down-regulation of MYC, a known oncogenic transcription factor and contributor to the pathogenesis in certain cancer types, has been linked to BET inhibitor (BETi) treatment. In addition, resistance to BETis has only been examined in MYC-dependent cancers, with all forms of resistance involving re-expression of MYC, through several mechanisms. Previously, our lab has shown that lung adenocarcinoma (LAC) cells are inhibited by JQ1 through a mechanism independent of MYC down-regulation, identifying FOSL1 as a mediator of response. This suggests that the epigenetic landscape of cells from different origins and differentiation states influences response to JQ1. Therefore, I aim to investigate how LAC cells, independent of MYC down-regulation, acquire resistance to BET inhibition, to elucidate mechanisms of primary resistance and potential treatment strategies for LAC. Here, I establish resistance in two JQ1 sensitive LAC cell lines and demonstrate that MYC levels were not significantly altered, nor was FOSL1 expression reactivated in resistant lines, indicating a novel mechanism of resistance. Interestingly, resistant lines were still dependent on the BET protein BRD4, as demonstrated by siRNA knockdown, suggesting that BRD4 may drive resistance through regulating gene transcription independent of its acetyl-binding domain. Both resistant lines showed increased levels of phosphorylated BRD4, and also up-regulation of casein kinase 2 (CK2), a kinase previously shown to phosphorylate BRD4. Furthermore, combining JQ1 with a CK2 inhibitor showed synergistic effects in both resistant lines, with treatment leading to decreased levels of pBRD4. Overall, we have determined that LAC cells develop JQ1 resistance through mechanisms independent of MYC, identifying CK2 phosphorylation of BRD4 as a likely mechanism of resistance.

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