Related Experiment Video

Updated: Jun 18, 2026

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
10:09

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

Targeting the Fanconi anemia/BRCA pathway circumvents drug resistance in multiple myeloma

Danielle N Yarde1, Vasco Oliveira, Linda Mathews

  • 1Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612, USA.

Cancer Research
|November 26, 2009
PubMed

Insights

NF-kappaB subunits RelB/p50 activate the Fanconi anemia/BRCA (FA/BRCA) DNA repair pathway. Targeting this pathway enhances chemotherapy response and overcomes drug resistance in multiple myeloma.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The Fanconi anemia/BRCA (FA/BRCA) pathway is crucial for DNA repair and influences cancer drug response.
  • FA/BRCA genes are overexpressed in melphalan-resistant multiple myeloma, causing drug resistance.
  • Transcriptional regulation of the FA/BRCA pathway remains largely unknown.

Purpose of the Study:

  • To elucidate the transcriptional regulation of the FA/BRCA pathway.
  • To identify novel regulators of FA/BRCA in multiple myeloma.
  • To explore therapeutic strategies targeting FA/BRCA for overcoming drug resistance.

Main Methods:

  • Investigated the role of NF-kappaB subunits (RelB/p50) in regulating FA/BRCA.
  • Analyzed constitutive phosphorylation of IkappaB kinase alpha.
  • Assessed the impact of NF-kappaB inhibition (siRNA, BMS-345541) and proteasome inhibition (bortezomib) on FA/BRCA expression and FANCD2.
  • Evaluated drug sensitivity in multiple myeloma cells and patient samples.

Main Results:

  • Identified NF-kappaB subunits RelB/p50 as transcriptional activators of the FA/BRCA pathway.
  • Demonstrated constitutive IkappaB kinase alpha phosphorylation in melphalan-resistant myeloma cells, affecting FANCD2.
  • Showed that inhibiting NF-kappaB or proteasome function reduces FA/BRCA and FANCD2 expression, enhancing melphalan sensitivity.
  • Confirmed bortezomib decreases FA/BRCA expression in multiple myeloma patients.

Conclusions:

  • NF-kappaB transcriptionally regulates the FA/BRCA pathway.
  • Targeting Fanconi anemia-mediated DNA repair can enhance chemotherapeutic response.
  • This provides a strategy to circumvent drug resistance in multiple myeloma patients.

More Related Videos

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

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

Related Concept Videos

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...
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...
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...
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...
Treatment Resistent Cancers02:56

Treatment Resistent 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...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...