BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression

Related Experiment Video

Updated: Dec 13, 2025

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
10:44

Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

13.6K

Thomas E C Cummin1, Kerry L Cox1, Tom D Murray1

  • 1Antibody and Vaccine Group, Centre for Cancer Immunology.

Blood Advances
|July 28, 2020
PubMed

Insights

Novel nonbenzodiazepine bromodomain and extraterminal (BET) inhibitors show promise for treating aggressive lymphomas. Combining these BET inhibitors with venetoclax restores anti-tumor activity in diffuse large B-cell lymphoma by overcoming BCL-2 resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • MYC oncogenic network is a therapeutic target in lymphoma, but direct inhibitors are challenging to develop.
  • Bromodomain and extraterminal (BET) inhibitors modulate MYC, but current benzodiazepine-derivatives show limited efficacy and toxicity in relapsed/refractory lymphoma.
  • Need for novel nonbenzodiazepine BET inhibitors and better mechanistic understanding for lymphoma treatment.

Purpose of the Study:

  • To characterize the response of aggressive MYC-driven lymphomas to two nonbenzodiazepine BET inhibitors, PLX51107 and PLX2853.
  • To investigate the mechanism of action of these BET inhibitors, including BIM-dependent apoptosis and miR-17∼92 repression.
  • To evaluate the efficacy of combining BET inhibitors with venetoclax in diffuse large B-cell lymphoma (DLBCL) models.

Main Methods:

  • Treatment of murine Eµ-myc lymphomas with PLX51107 and PLX2853.
  • Assessment of apoptosis, in vivo therapy, BIM expression, and miR-17∼92 levels.
  • Evaluation of the impact of exogenous BCL-2 expression and coadministration of BET inhibitors with ABT199/venetoclax in DLBCL cell lines.

Main Results:

  • Both nonbenzodiazepine BET inhibitors induced BIM-dependent apoptosis and in vivo therapy in murine lymphomas, linked to miR-17∼92 repression.
  • PLX2853 demonstrated enhanced potency compared to PLX51107.
  • Exogenous BCL-2 expression blocked BET inhibitor-induced apoptosis; BET inhibitors were ineffective in DLBCL cell lines due to high BCL-2, but BIM upregulation and miR-17∼92 repression persisted.
  • Coadministration of BET inhibitors and venetoclax restored cell death and in vivo therapy in DLBCL models.

Conclusions:

  • BIM-dependent apoptosis is a critical mechanism of action for nonbenzodiazepine BET inhibitors in MYC-driven lymphomas.
  • High BCL-2 expression confers resistance to BET inhibitors in DLBCL.
  • Combination therapy with BET inhibitors and BH3 mimetics like venetoclax can achieve effective tumor control in DLBCL.

More Related Videos

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation15:04

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation

Published on: January 19, 2019

12.6K
In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis07:25

In Vitro Methods for Comparing Target Binding and CDC Induction Between Therapeutic Antibodies: Applications in Biosimilarity Analysis

Published on: May 4, 2017

18.1K

Related Concept Videos

The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.9K
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.7K
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...
8.5K
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.4K
Drugs that Destabilize Microtubules01:10

Drugs that Destabilize Microtubules

Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
3.4K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
1.6K