Related Experiment Video

Updated: Sep 16, 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

651

Cytidine diphosphate diacylglycerol synthase 2 is a synthetic lethal target in mesenchymal-like cancers

Tim Arnoldus1, Alex van Vliet1, Onno B Bleijerveld2

  • 1Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Nature Genetics
|July 4, 2025
PubMed

Insights

Synthetic lethal interactions identified a new target in cancer therapy. Targeting cytidine diphosphate diacylglycerol synthase 2 (CDS2) shows promise for treating mesenchymal-like cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Synthetic lethal interactions (SLIs) are therapeutically explored based on genomic alterations in cancer.
  • Investigating SLIs based on differential RNA expression in cancer and normal tissues is crucial for identifying novel therapeutic targets.

Purpose of the Study:

  • To uncover cancer-specific SLIs by analyzing functional genomic and gene expression data.
  • To identify potential therapeutic targets in mesenchymal-like cancers based on SLIs.

Main Methods:

  • Computational analysis of functional genomic and gene expression resources.
  • Genome-wide CRISPR-Cas9 knockout screens in CDS1-negative cancer cells.
  • Assessing the essentiality of CDS2 for cell survival in relation to CDS1 expression.

Main Results:

  • A cancer-specific SLI was discovered between cytidine diphosphate diacylglycerol synthase 1 (CDS1) and CDS2.
  • CDS2 is essential for cell survival in mesenchymal-like cancers with low or absent CDS1 expression.
  • The CDS1-2 SLI disrupts lipid homeostasis, leading to apoptosis, and shows robustness against escape mechanisms.

Conclusions:

  • CDS2 is a pharmacologically tractable target in mesenchymal-like cancers.
  • The synthetic lethality is dependent on CDS2 dosage and catalytic activity.
  • Targeting CDS2 offers a promising therapeutic strategy for a significant proportion of cancers.

More Related Videos

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions07:40

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

Published on: May 27, 2021

4.3K
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.3K

Related Concept Videos

M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.7K
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
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K