Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex
Open accessAbstract
Targeting the dysregulated BRAF–MEK–ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment. In preclinical models, MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation, and p300 that drives transcriptional adaptation. Inhibition of the P-TEFb–associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts, and syngeneic mouse TNBC models. Pharmacologic targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance. Significance: Widespread transcriptional adaptation to pharmacologic MEK inhibition was observed in TNBC patient tumors. In preclinical models, MEK inhibition induces dramatic genome-wide modulation of chromatin, in the form of de novo enhancer formation and enhancer remodeling. Pharmacologic targeting of P-TEFb complex members at enhancers is an effective strategy to durably inhibit such adaptation. Cancer Discov; 7(3); 302–21. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 235
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Pretreatment biopsies matched to post-treatment surgical specimens showed overall concordance of transcriptional kinase response to trametinib, with FRK highest mean increase and cytoplasmic BMX highest mean decrease.
“Pretreatment biopsies matched to post-treatment surgical specimens showed overall concordance of the transcriptional kinase response to trametinib, with FRK (Tchem) exhibiting the highest mean increase and cytoplasmic BMX (also Tchem) exhibiting the highest mean decrease among patients in response to a 7-day drug treatment.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [75]
The Results section, “MEK inhibition induces a transcriptomic/kinome response in patient TNBC tumors” (page unavailable), reports concordant transcriptional responses in four matched basal-like tumors, with FRK showing the highest mean increase and BMX the highest mean decrease after seven days of trametinib. It does not describe BMX as cytoplasmic or label FRK and BMX “Tchem”; it also limits the concordance finding to patients 1, 2, 3, and 5, rather than all patients. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn TNBC tumours, members of the understudied Tbio and Tdark kinome are co-regulated transcriptionally with Tclin and Tchem kinases in a dynamic adaptive response to targeted inhibition.
“These findings demonstrate that in TNBC tumours in patients, members of the understudied Tbio and Tdark kinome are co-regulated transcriptionally with kinases from the Tclin and Tchem category, in a dynamic adaptive response to targeted inhibition.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [75]
The Results section, “MEK inhibition induces a transcriptomic/kinome response in patient TNBC tumors” (page unavailable), reports transcriptional changes in multiple kinases after seven days of trametinib treatment. It does not classify those kinases as Tbio, Tdark, Tclin, or Tchem or establish co-regulation between those categories, so that specific part of the claim is unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAmong kinases transcriptionally altered in TNBC tumours were understudied kinases MRCK-γ, PRKACB, STK32B and LTK.
“Among the kinases transcriptionally altered in the TNBC tumours were several understudied kinases, including MRCK-γ (also known as CDC42BPG), PRKACB, STK32B and leukocyte tyrosine kinase receptor (LTK).”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [75]
The Results section on distinct basal-like and claudin-low kinome signatures identifies CDC42BPG (MRCK-γ) as upregulated in both patient TNBC tumours and cell lines after MEK inhibition. The paper also reports broader transcriptional changes in tumour kinases, but our copy does not identify PRKACB, STK32B or LTK as altered, or describe the listed kinases as understudied (pages not provided). (LLM, conf=0.85)
Experimental — accuracy not yet measuredA recent clinical study assessed trametinib response in TNBC patients.
“The potential therapeutic importance of Tbio and Tdark kinases in the kinome is highlighted by a recent clinical study that assessed the response to trametinib, a MEK1 and MEK2 inhibitor, in TNBC patients75.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [75]
BET proteins facilitate chromatin remodeling and transcriptional adaptation necessary for establishing the DTP state in response to MEK and PI3K inhibitors in breast cancer models, which can be prevented by the BET inhibitor JQ1.
“Several studies have revealed that BET proteins facilitate chromatin remodeling and transcriptional adaptation necessary for establishing the DTP state in response to MEK and PI3K inhibitors in breast cancer models, which can be prevented by the BET inhibitor JQ1 [66,74].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [74]
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Kitajima, S., Asahina, H., Chen, T., Guo, S., Quiceno, L. G., Cavanaugh, J. D., Merlino, A. A., Tange, S., Terai, H., Kim, J. W., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.08.009 · Cited by 75 · see citing works
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- Authors
- Zawistowski, J. S., Bevill, S. M., Goulet, D. R., Stuhlmiller, T. J., Beltran, A. S., Olivares-Quintero, J. F., Singh, D., Sciaky, N., Parker, J. S., Rashid, N. U., Chen, X., Duncan, J. S., Whittle, M. C., Angus, S. P., Velarde, S. H., Golitz, B. T., He, X., Santos, C., Darr, D. B., Gallagher, K., Graves, L. M., Perou, C. M., Carey, L. A., Earp, H. S., & Johnson, G. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- 1Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
- 5Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
- Corresponding author
- Johnson, Gary L.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2017-03-01
- Volume
- 7
- Issue
- 3
- Pages
- 302-321
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5340640
- OpenAlex
- W2576619896
- Cited by
- 180
- References
- 56
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 17 · 2023: 15 · 2022: 18 · 2021: 47 · 2020: 13 · 2019: 14 · 2018: 17 · 2017: 15
- FWCI
- 6.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Susan G. Komen for the Cure
- National Cancer Institute (P50CA058223, P30CA016086)
- National Institute of General Medical Sciences (R01GM101141, F31GM116534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- MEK inhibition, trametinib, triple-negative breast cancer, adaptive resistance, enhancer remodeling, CBP/p300, transcriptional adaptation, chromatin remodeling, H3K27 acetylation
- MeSH terms
- Discoidin Domain Receptor 1, Bromodomain Containing Proteins, Animals, Antineoplastic Agents, Azepines, Drug Synergism, Enhancer Elements, Genetic, Female, Heterocyclic Compounds, 4 or More Rings, Humans, Mice, Inbred BALB C, Nuclear Proteins, Pyridones, Pyrimidinones, Transcription Factors, Triazoles, Mice, SCID, Cell Cycle Proteins, Drug Resistance, Neoplasm, DNA Methylation, Xenograft Model Antitumor Assays, RNA Interference, Positive Transcriptional Elongation Factor B, Epigenesis, Genetic, Cell Line, Tumor, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Molecular Targeted Therapy, Triple Negative Breast Neoplasms
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