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Cited by 327

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Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins

Lockwood, William W., Zejnullahu, Kreshnik, Bradner, James E., Varmus, Harold·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1216363109
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Abstract

Bromodomain and extra terminal domain (BET) proteins function as epigenetic signaling factors that associate with acetylated histones and facilitate transcription of target genes. Inhibitors targeting the activity of BET proteins have shown potent antiproliferative effects in hematological cancers through the suppression of c -MYC and downstream target genes. However, as the epigenetic landscape of a cell varies drastically depending on lineage, transcriptional coactivators such as BETs would be expected to have different targets in cancers derived from different cells of origin, and this may influence the activity and mechanism of action of BET inhibitors. To test this hypothesis, we treated a panel of lung adenocarcinoma (LAC) cell lines with the BET inhibitor JQ1 and found that a subset is acutely susceptible to BET inhibition. In contrast to blood tumors, we show that LAC cells are inhibited by JQ1 through a mechanism independent of c-MYC down-regulation. Through gene expression profiling, we discovered that the oncogenic transcription factor FOSL1 and its targets are suppressed by JQ1 in a dose-dependant manner. Knockdown of BRD4 also decreased FOSL1 levels, and inhibition of FOSL1 phenocopied the effects of JQ1 treatment, suggesting that loss of this transcription factor may be partly responsible for the cytotoxic effects of BET inhibition in LAC cells, although ectopic expression of FOSL1 alone did not rescue the phenotype. Together, these findings suggest that BET inhibitors may be useful in solid tumors and that cell-lineage–specific differences in transcriptional targets of BETs may influence the activity of inhibitors of these proteins in different cancer types.

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  • Mutant EGFR, despite being constitutively active, is subjected to trafficking but is often impaired in its interactions with Cbl, resulting in defective ubiquitination and degradation.

    “Mutant EGFR, despite being constitutively active, is also subjected to trafficking i.e. internalization and localization to the endosomes; but is often impaired in its interactions with Cbl, an E3 ubiquitin ligase, resulting in defective ubiquitination and degradation30.”

    From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [30]

  • Typically, after ligand stimulation, activated cell-surface EGFR becomes internalized, localized in early endosomes and later in lysosomes, which mediate its degradation.

    “Typically, after stimulation of EGFR by ligand, the activated cell-surface receptor becomes internalized, localized in early endosomes and later in lysosomes, which mediate its degradation and ensure normal cellular homeostasis30.”

    From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [30]

  • EGFR localized to early endosomes can be recycled back to the plasma membrane instead of proceeding to the lysosome, leading to sustained protein half-life and prolonged signaling.

    “EGFR localized to the early endosomes can also be recycled back to the plasma membrane instead of proceeding to the lysosome, leading to sustained protein half-life and prolonged signaling30.”

    From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [30]

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Research works printed but not linked: 20

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Metadata

Authors
Lockwood, W. W., Zejnullahu, K., Bradner, J. E., & Varmus, H.
Affiliations
  • Cancer Biology and Genetics Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
  • Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215; and
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-11-05
Volume
109
Issue
47
Pages
19408-19413
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1216363109
Cited by
327
References
4
Language
en

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