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| Status |
Public on Apr 07, 2021 |
| Title |
Resistance to BET inhibitors in lung adenocarcinoma is mediated by casein kinase phosphorylation of BRD4 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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- 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 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 re-activation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.
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| Overall design |
Two lung adenocarcinoma cell lines initially sensitive to JQ1 were treated with escalating doses of the drug until resistant cells were selected (Resistant). In parallel, the parental cells were cultured in vehicle as a control (DMSO). In addition, control cells were treated with JQ1 for 6hours. All treatment conditions were done in triplicate before RNA was extracted and profiled.
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| Contributor(s) |
Lockwood WW |
| Citation(s) |
33712563 |
| Submission date |
Jan 14, 2021 |
| Last update date |
Apr 07, 2021 |
| Contact name |
William Lockwood |
| E-mail(s) |
wlockwood@bccrc.ca
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| Phone |
6046758264
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| Organization name |
BC Cancer
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| Department |
Integrative Oncology
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| Street address |
675 West 10th Avenue
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| City |
Vancouver |
| State/province |
British Columbia |
| ZIP/Postal code |
V5Z 1L3 |
| Country |
Canada |
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| Platforms (1) |
| GPL15207 |
[PrimeView] Affymetrix Human Gene Expression Array |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA692132 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE164813_RAW.tar |
35.5 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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