Related Experiment Video

Updated: Jan 19, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

15.2K

Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting

B A Carneiro1,2, K A Collier3, R J Nagy4

  • 1Developmental Therapeutics Program, Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

JCO Precision Oncology
|September 11, 2019
PubMed

Insights

PARP inhibitors are effective for BRCA2-mutated prostate cancer. Acquired resistance can emerge due to BRCA2 reversion mutations, detectable by circulating tumor DNA (ctDNA) analysis.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • PARP1/2 inhibitors (PARPi) show efficacy in BRCA2-deficient tumors.
  • Olaparib is FDA-designated for metastatic castration-resistant prostate cancer (CRPC) with BRCA1/2 or ATM mutations.
  • Acquired resistance to PARPi can develop through tumor-specific BRCA2 mutations that restore homologous recombination.

Purpose of the Study:

  • To report a case of metastatic CRPC with acquired olaparib resistance due to biallelic BRCA2 reversion mutations.
  • To analyze the frequency of BRCA2 reversion mutations in a large cohort of prostate cancer patients.
  • To assess the utility of ctDNA analysis for detecting resistance-driving reversion mutations.

Main Methods:

  • Case study of metastatic CRPC with germline BRCA2 mutation and acquired olaparib resistance.
  • Retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis.
  • Detection of germline and somatic BRCA2 reversion mutations using circulating tumor DNA (ctDNA).

Main Results:

  • A case of metastatic CRPC with acquired olaparib resistance was linked to biallelic BRCA2 reversion mutations.
  • Germline BRCA2 mutations were found in 1.6% of the analyzed prostate cancer cohort.
  • Among germline BRCA2-positive patients treated with platinum chemotherapy or PARPi, 40% exhibited reversion mutations.

Conclusions:

  • This study documents the prevalence of reversion mutations in prostate cancer patients with BRCA mutations.
  • ctDNA analysis can detect reversion mutations that drive resistance to PARPi.
  • Early detection of resistance mechanisms via ctDNA holds potential for guiding treatment strategies.

More Related Videos

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells09:24

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

Published on: August 12, 2015

9.5K
Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses08:36

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

Published on: October 24, 2019

11.7K

Related Concept Videos

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Emergence of genetic resistance against kinase inhibitor therapy poses significant challenge for effective cancer therapy. Identification and characterization of resistant mutations against a newly developed drug helps in better clinical management and next generation drug design. Here, we describe our protocol for in vitro screening and validation of resistant...
15.2K
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells09:24

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

Gene silencing by siRNA represents a convenient experimental strategy to analyze BRCA2-dependent biological functions with immediate implications to better understand cancer biology. A method to efficiently silence BRCA2, along with the experimental procedure to detect and quantify changes in BRCA2 protein expression by immunoblotting in human cell lines, is presented.
9.5K
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...
14.6K
Mutations01:39

Mutations

Overview
94.4K
Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses08:36

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

Presented here is a protocol to study pharmacological responses in prostate epithelial organoids. Organoids closely resemble in vivo biology and recapitulate patient genetics, making them attractive model systems. Prostate organoids can be established from wildtype prostates, genetically engineered mouse models, benign human tissue, and advanced prostate...
11.7K
Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation07:17

Wild-type Blocking PCR Combined with Sanger Sequencing for Detection of Low-frequency Somatic Mutation

This article introduces the application of a low-frequency detection method based on Sanger sequencing in angioimmunoblastic lymphoma. Provide a basis for applying this method to other...
1.8K