Related Experiment Video

Updated: Mar 8, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

6.6K

Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb

Jon S Zawistowski1, Samantha M Bevill1, Daniel R Goulet1

  • 1Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.

Cancer Discovery
|January 22, 2017
PubMed

Insights

Targeting the BRAF-MEK-ERK pathway is crucial for cancer treatment. Inhibiting MEK in triple-negative breast cancer (TNBC) triggers resistance, but combining MEK inhibitors with P-TEFb targeting drugs overcomes this by blocking adaptive resistance mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The BRAF-MEK-ERK pathway is a key target in cancer therapy.
  • Resistance to MEK inhibitors, particularly in triple-negative breast cancer (TNBC), often involves adaptive bypass mechanisms.
  • Trametinib, a MEK inhibitor, induces significant transcriptional changes in TNBC, including receptor tyrosine kinase (RTK) upregulation.

Purpose of the Study:

  • To investigate the mechanisms of resistance to MEK inhibition in TNBC.
  • To explore strategies for overcoming MEK inhibitor resistance by targeting adaptive transcriptional responses.
  • To evaluate the efficacy of combining MEK inhibitors with P-TEFb complex inhibitors.

Main Methods:

  • Analysis of tumor samples from TNBC patients before and after trametinib treatment.
  • Preclinical studies in TNBC models to assess genome-wide enhancer formation and chromatin remodeling.
  • Inhibition of BRD4 and CBP/p300, components of the P-TEFb complex, to block enhancer seeding.
  • Evaluation of BRD4 bromodomain inhibitors in combination with trametinib.

Main Results:

  • MEK inhibition by trametinib in TNBC patients induced widespread transcriptional adaptation, including RTK upregulation.
  • Preclinical models showed MEK inhibition promoted genome-wide enhancer formation via BRD4, MED1, H3K27 acetylation, and p300.
  • Inhibiting BRD4 and CBP/p300 prevented enhancer seeding and RTK upregulation.
  • BRD4 bromodomain inhibitors combined with trametinib achieved sustained tumor growth inhibition in TNBC models.

Conclusions:

  • Pharmacologic MEK inhibition in TNBC leads to adaptive transcriptional changes and resistance.
  • MEK inhibition induces significant chromatin remodeling and enhancer formation.
  • Targeting P-TEFb complex members, such as BRD4 and CBP/p300, alongside MEK inhibitors is a promising strategy to overcome adaptive resistance in TNBC.

More Related Videos

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes09:16

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Published on: June 3, 2018

7.8K
Dissection of Enhancer Function Using Multiplex CRISPR-based Enhancer Interference in Cell Lines10:46

Dissection of Enhancer Function Using Multiplex CRISPR-based Enhancer Interference in Cell Lines

Published on: June 2, 2018

9.9K

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
8.9K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
8.2K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
7.6K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
18.9K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
5.0K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
9.0K