Related Experiment Video

Updated: May 16, 2026

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
09:24

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor

Louise J Barber1, Shahneen Sandhu, Lina Chen

  • 1Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

The Journal of Pathology
|November 21, 2012
PubMed

Insights

Clinical resistance to PARP inhibitors (PARPi) in BRCA-deficient tumors can arise from secondary BRCA2 mutations. These mutations restore BRCA2 protein function, enabling tumor cells to evade PARPi treatment.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • PARP inhibitors (PARPi) are a promising treatment for BRCA1/BRCA2-deficient tumors, leveraging synthetic lethality.
  • Clinical resistance to PARPi has been observed, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms of clinical resistance to the PARP inhibitor olaparib in patients with BRCA-deficient tumors.
  • To identify genetic alterations responsible for acquired resistance to olaparib.

Main Methods:

  • Analysis of tumor biopsies from patients who initially responded to olaparib but later developed resistance.
  • Massively parallel DNA sequencing of treatment-naive and post-treatment tumor samples.

Main Results:

  • Identification of tumor-specific BRCA2 secondary mutations in olaparib-resistant metastases.
  • These secondary mutations were found to restore the full-length BRCA2 protein.
  • Restored BRCA2 function is the likely cause of olaparib resistance.

Conclusions:

  • Secondary mutations in BRCA2 can lead to acquired resistance to olaparib in BRCA-deficient tumors.
  • Restoration of BRCA2 protein function is a key mechanism driving PARPi resistance.
  • Understanding these resistance mechanisms is crucial for developing future therapeutic strategies.

More Related Videos

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA108:53

Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1

Published on: February 17, 2011

gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair08:15

gDNA Enrichment by a Transposase-based Technology for NGS Analysis of the Whole Sequence of BRCA1, BRCA2, and 9 Genes Involved in DNA Damage Repair

Published on: October 6, 2014

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...
Mismatch Repair01:20

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
Mismatch Repair01:36

Mismatch Repair

Overview
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...
Cancers Originate from Somatic Mutations in a Single Cell02:21

Cancers Originate from Somatic Mutations in a Single Cell

Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...