Related Experiment Video

Updated: Aug 6, 2026

Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
14:51

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

Published on: June 17, 2022

Multiple mechanisms underlie resistance of leukemia cells to Apo2 Ligand/TRAIL

Jinrong Cheng1, Bonnie L Hylander, Maria R Baer

  • 1Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Molecular Cancer Therapeutics
|August 8, 2006
PubMed

Insights

Leukemia cells can resist tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy through various mechanisms. Researchers identified decreased DR4 receptor levels or loss of procaspase-8 due to gene mutation as key resistance factors.

Area of Science:

  • Cancer Biology
  • Molecular Oncology
  • Apoptosis Research

Background:

  • Targeting death receptors with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) offers selective cancer cell killing.
  • Leukemia cells often display resistance to TRAIL-based therapies, limiting their clinical efficacy.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying resistance in leukemia cells to the zinc-bound form of Apo2 ligand (Apo2L)/TRAIL.
  • To characterize the differing resistance mechanisms in Apo2L/TRAIL-resistant HL60 clones.

Main Methods:

  • Isolation of Apo2L/TRAIL-resistant HL60 clones through selective pressure.
  • Characterization of resistance mechanisms, including assessment of death receptor expression (DR4, DR5) and caspase-8 (CASP-8) gene mutation analysis.

Main Results:

  • Identified distinct resistance mechanisms in different HL60 clones.
  • One clone showed decreased DR4 levels but remained sensitive to histidine-tagged TRAIL, indicating differential receptor contribution.
  • Other clones lost procaspase-8 expression due to a novel Leu(22)-->Phe(22) point mutation in the CASP-8 gene.

Conclusions:

  • Leukemia cells exhibit diverse mechanisms of resistance to Apo2L/TRAIL.
  • Understanding these distinct resistance pathways is crucial for developing more effective TRAIL-based cancer therapies.

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...
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...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
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 specific...