Abstract
Targeting the epigenome to modulate gene expression programs driving cancer development has emerged as an exciting avenue for therapeutic intervention. Pharmacological inhibition of the bromodomain and extraterminal (BET) family of chromatin adapter proteins has proven effective in this regard, suppressing growth of diverse cancer types mainly through downregulation of the c-MYC oncogene, and its downstream transcriptional program. While initially effective, resistance to BET inhibitors (BETi) typically occurs through mechanisms that reactivate MYC expression. We have previously shown that lung adenocarcinoma (LAC) is inhibited by JQ1 through suppression of FOSL1, suggesting that the epigenetic landscape of tumor cells from different origins and differentiation states influences BETi response. Here, we assessed how these differences affect mechanisms of BETi resistance through the establishment of isogenic pairs of JQ1 sensitive and resistant LAC cell lines. We found that resistance to JQ1 in LAC occurs independent of FOSL1 while MYC levels remain unchanged between resistant cells and their JQ1-treated parental counterparts. Furthermore, while epithelial–mesenchymal transition (EMT) is observed upon resistance, TGF-β induced EMT did not confer resistance in JQ1 sensitive LAC lines, suggesting this is a consequence, rather than a driver of BETi resistance in our model systems. Importantly, siRNA knockdown demonstrated that JQ1 resistant cell lines are still dependent on BRD4 expression for survival and we found that phosphorylation of BRD4 is elevated in resistant LACs, identifying casein kinase 2 (CK2) as a candidate protein mediating this effect. Inhibition of CK2, as well as downstream transcriptional targets of phosphorylated BRD4—including AXL and activators of the PI3K pathway—synergize with JQ1 to inhibit BETi resistant LAC. Overall, this demonstrates that the mechanism of resistance to BETi varies depending on cancer type, with LAC cells developing JQ1 resistance independent of MYC regulation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.
Highlights
Epigenomic alterations are important drivers of tumorigenesis, modifying chromatin structure and the expression of key genes that influence cell phenotype
JQ1 resistant lung adenocarcinoma (LAC) cell lines are still dependent on BRD4 for survival we aimed to assess whether the JQ1 resistant cell lines were still dependent on bromodomain and extraterminal (BET) proteins for survival
We found that resistance to JQ1 is not driven by reactivation of FOSL1 or activation of MYC—two known targets of BRD4 inhibition—or by epithelial–mesenchymal transition (EMT), which was unable to induce resistance to JQ1
Summary
Epigenomic alterations are important drivers of tumorigenesis, modifying chromatin structure and the expression of key genes that influence cell phenotype. BRD4 has been shown to occupy the enhancers of actively transcribed genes, at large super-enhancer regions that are associated with the Calder et al Oncogenesis (2021)10:27 expression of transcription factors and other genes that drive cancer and tissue-specific cell development[6] This role in mediating oncogenic potential combined with its recurrent genomic alteration in a subset of cancers, including NUT midline carcinoma, has increased interest in targeting BRD4 to inhibit diverse cancer types[7]. This effect was independent of driver gene mutation status as both EGFR and KRAS mutant LAC cell lines demonstrated differential sensitivity to JQ1 corresponding to FOSL1 suppression[22] These findings suggest that the tissue origin and resulting epigenetic landscape of a cell is a crucial determinant in mediating the response and mechanism of action of BET protein inhibitors, an important consideration for the future development of therapies targeting epigenetic proteins in cancer cells. Osteosarcoma has demonstrated MYC-independent sensitivity to BET inhibition, with FOSL1 as the likely downstream regulatory gene in this context as well[23]
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