Related Experiment Video

Updated: Jan 22, 2026

Recombineering Homologous Recombination Constructs in Drosophila
14:23

Recombineering Homologous Recombination Constructs in Drosophila

Published on: July 13, 2013

19.7K

Loss of MAP3K7 Sensitizes Prostate Cancer Cells to CDK1/2 Inhibition and DNA Damage by Disrupting Homologous

Satoshi Washino1, Leah C Rider1, Lina Romero1

  • 1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Molecular Cancer Research : MCR
|July 14, 2019
PubMed

Insights

Loss of MAP3K7 in prostate cancer disrupts DNA repair, making tumors sensitive to CDK inhibitors like dinaciclib. This finding offers new therapeutic strategies for aggressive prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Combined loss of CHD1 and MAP3K7 drives aggressive prostate cancer through unknown mechanisms.
  • Direct targeting of lost CHD1 and MAP3K7 genes is not feasible in prostate cancer.

Purpose of the Study:

  • To identify druggable targets and signaling pathways altered by the loss of CHD1 and MAP3K7 in prostate cancer using a computational systems pharmacology approach.
  • To investigate the therapeutic potential of targeting CDK1 and CDK2 in prostate cancer cells with combined CHD1 and MAP3K7 loss.

Main Methods:

  • Comparative analysis of The Cancer Genome Atlas (TCGA) patient samples to identify gene expression differences between prostate cancers with and without CHD1/MAP3K7 loss.
  • Utilized the TRAP (Targeted Response Assessment of Pathways) computational approach to predict druggable targets.
  • In vitro validation using mouse and human prostate cell lines with gene knockdown and treatment with CDK inhibitors (dinaciclib).
  • Assessed DNA repair inhibition through analysis of homologous recombination (HR) repair gene expression, protein phosphorylation, and DNA damage foci.

Main Results:

  • The computational analysis identified CDK1 and CDK2 as prioritized druggable targets.
  • Dinaciclib selectively exhibited antiproliferative and cytotoxic effects on mouse prostate cells with suppressed Chd1 and Map3k7.
  • Dinaciclib demonstrated stronger efficacy in Map3k7-suppressed cells, independent of Chd1 status.
  • Dinaciclib inhibited homologous recombination (HR) repair by reducing expression of key HR genes, blocking BRCA1 phosphorylation, and decreasing RAD51 foci.
  • Dinaciclib-induced HR disruption was confirmed in human prostate cells with MAP3K7 knockdown.
  • Combination therapy of dinaciclib with DNA-damaging agents or a PARP inhibitor enhanced cytotoxicity in Map3k7-suppressed cells.

Conclusions:

  • Loss of MAP3K7 is a significant driver of drug response in prostate cancer by disrupting HR repair pathways.
  • Targeting CDK1/CDK2 with inhibitors like dinaciclib represents a promising therapeutic strategy for prostate cancers with MAP3K7 loss.
  • Combined inhibition of HR repair and DNA-damaging agents may enhance treatment efficacy for specific prostate cancer subtypes.

More Related Videos

Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays04:07

Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays

Published on: February 24, 2023

2.2K
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

15.0K

Related Concept Videos

Homologous Recombination02:31

Homologous Recombination

The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
62.8K
Homologous Recombination02:31

Homologous Recombination

6.3K
Recombinant DNA01:09

Recombinant DNA

Overview
101.8K
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
3.1K
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
10.0K
Loss of Carboxy Group as CO2: Decarboxylation of β-Ketoacids01:02

Loss of Carboxy Group as CO2: Decarboxylation of β-Ketoacids

Carboxylic acids, upon heating, undergo a decarboxylation reaction by releasing carbon dioxide gas. Monocarboxylic acids do not undergo decarboxylation easily. However, a silver salt of carboxylic acid reacts with bromine or iodine under high temperature to release carbon dioxide gas and forms halide with one less carbon. This reaction is called the Hunsdiecker reaction.
3.9K