Related Experiment Video

Updated: Aug 30, 2025

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
07:23

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

Published on: May 30, 2025

567

VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system

Jonathan So1,2, Nathaniel W Mabe2,3, Bernhard Englinger2,3,4

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.

JCI Insight
|August 30, 2022
PubMed

Insights

Cancer cells in the nervous system rely on the nuclear kinase vaccinia-related kinase 1 (VRK1) for survival. Targeting VRK1 offers a new strategy for treating gliomas and neuroblastomas, especially when VRK2 expression is low.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Collateral lethality is a concept where the loss of one gene or protein makes cancer cells dependent on its related gene or protein.
  • Understanding these dependencies can reveal novel therapeutic targets for cancer treatment.

Purpose of the Study:

  • To identify genes essential for the survival of nervous system cancers.
  • To explore the synthetic lethal relationship between vaccinia-related kinase 1 (VRK1) and its paralog VRK2.
  • To investigate VRK1 as a potential therapeutic target in specific cancer types.

Main Methods:

  • Genome-scale CRISPR/Cas9 loss-of-function screens were performed on over 900 cancer cell lines.
  • RNA sequencing was utilized to analyze gene expression profiles.
  • DNA methylation analysis of the VRK2 promoter was conducted.

Main Results:

  • Cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, demonstrated dependency on VRK1 for in vivo survival.
  • VRK1 dependency inversely correlated with the expression of its paralog, VRK2.
  • VRK2 knockout sensitized cells to VRK1 loss, while VRK2 overexpression enhanced cell fitness upon VRK1 loss.
  • DNA methylation of the VRK2 promoter was linked to low VRK2 expression in gliomas and neuroblastomas.

Conclusions:

  • VRK1 is essential for the survival of adult and pediatric gliomas and neuroblastomas.
  • The study identifies a synthetic lethal interaction between VRK1 and VRK2.
  • VRK1 represents a potential synthetic lethal target in VRK2 promoter-methylated gliomas and neuroblastomas.
Keywords:
Brain cancerCancerMolecular geneticsOncology

More Related Videos

Real-Time Quantitative Measurement of Tumor Cell Migration and Invasion Following Synthetic mRNA Transfection11:00

Real-Time Quantitative Measurement of Tumor Cell Migration and Invasion Following Synthetic mRNA Transfection

Published on: June 23, 2023

1.2K
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy08:51

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy

Published on: April 3, 2018

9.2K

Related Concept Videos

Rous Sarcoma Virus (RSV) and Cancer01:03

Rous Sarcoma Virus (RSV) and Cancer

Rous Sarcoma virus or RSV was discovered by F. Peyton Rous in the year 1911 as a filterable transmissible agent that could cause tumors in chickens. He won a Nobel Prize for this discovery in 1966. His experiments clearly demonstrated that some cancers could be caused by infectious agents and led to the discovery of many more cancer-causing viruses in animals as well as humans.
RSV is a retrovirus that contains two copies of a plus-strand  RNA genome. Its genome consists of four main open...
5.3K
In-vitro Mutagenesis01:16

In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
14.2K
Mechanisms of Retrovirus-induced Cancers01:51

Mechanisms of Retrovirus-induced Cancers

Retroviruses are RNA viruses that have been shown to cause cancers in diverse species, including chickens, mice, cats, and monkeys. The RNA genomes of these viruses are first reverse-transcribed into single and then double-stranded DNA (dsDNA) copies. This dsDNA called proviral DNA then integrates into the host genome. Subsequently, the host cell transcribes the proviral DNA in concert with the chromosomal DNA. This leads to the production of viral RNA and proteins that assemble at the host...
5.2K
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...
7.8K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
4.3K