Related Experiment Video

Updated: Mar 8, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

11.2K

Pathways and mechanisms of venetoclax resistance

Prithviraj Bose1, Varsha Gandhi1,2, Marina Konopleva1

  • 1a Department of Leukemia , University of Texas MD Anderson Cancer Center , Houston , TX , USA.

Leukemia & Lymphoma
|February 1, 2017
PubMed

Insights

Venetoclax, a BCL-2 inhibitor, shows promise in leukemia but resistance can occur. Combining it with other targeted therapies may overcome resistance by targeting BCL-XL and MCL-1 proteins.

Area of Science:

  • Oncology
  • Molecular Biology
  • Translational Research

Background:

  • Venetoclax, a BCL-2 inhibitor, is approved for chronic lymphocytic leukemia and being studied in other cancers.
  • Resistance to venetoclax monotherapy is a significant clinical challenge.
  • BCL-XL and MCL-1 are identified as key determinants of resistance to venetoclax.

Purpose of the Study:

  • To review promising combination therapies with venetoclax to overcome resistance.
  • To highlight ongoing clinical trials of venetoclax combination therapies.
  • To discuss the role of BH3 profiling in refining targeted therapy strategies.

Main Methods:

  • Literature review of studies on venetoclax resistance mechanisms.
  • Analysis of clinical trial data for venetoclax combination therapies.
  • Discussion of emerging techniques in BH3 profiling.

Main Results:

  • BCL-XL and MCL-1 are critical for venetoclax resistance.
  • Combination strategies targeting BCL-2 family proteins show potential.
  • Several venetoclax combinations are currently in clinical trials.

Conclusions:

  • Targeting BCL-XL and MCL-1 alongside BCL-2 is a rational approach to enhance venetoclax efficacy.
  • Further development of selective BCL-XL and MCL-1 inhibitors is crucial.
  • Refined BH3 profiling may personalize combination therapy selection.
Keywords:
BCL-2BCL-XLMCL-1Venetoclaxrational combinationsresistance

More Related Videos

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

7.7K
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype14:51

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype

Published on: June 17, 2022

3.7K

Related Concept Videos

Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.8K
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
76
Development of Antibiotic Resistance01:30

Development of Antibiotic Resistance

Antibiotic resistance is a major public health concern that arises when bacteria evolve mechanisms to withstand the effects of antibiotic treatments. This resistance can be intrinsic, acquired through genetic mutations, or transferred between bacteria via horizontal gene transfer. The development of antibiotic resistance poses significant challenges in treating bacterial infections and necessitates ongoing research to develop new therapeutic strategies.Intrinsic resistance occurs when bacterial...
1.7K
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...
6.3K
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...
9.0K
Delivery Pathways to the Lysosome01:36

Delivery Pathways to the Lysosome

Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
10.4K