Related Experiment Video

Updated: May 29, 2025

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

Published on: May 27, 2021

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Synthetic lethality of mRNA quality control complexes in cancer

Vivian Prindle1, Adam E Richardson1, Kimberly R Sher1

  • 1AbbVie, North Chicago, IL, USA.

Nature
|February 5, 2025
PubMed

Insights

Synthetic lethality identifies new cancer targets. Targeting the PELO-HBS1L and SKI complexes inhibits tumor growth by exploiting cancer cell vulnerabilities.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Synthetic lethality is a precision cancer treatment strategy.
  • PARP inhibitors are a successful example of synthetic lethality.
  • Several novel targets are advancing in clinical trials.

Purpose of the Study:

  • Identify novel synthetic lethal interactions in human cancer.
  • Investigate the PELO-HBS1L and SKI complex interaction within the mRNA quality control pathway.
  • Determine the therapeutic potential of targeting this interaction.

Main Methods:

  • Analysis of distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumors.
  • Characterization of the PELO-HBS1L and SKI complex interplay.
  • Assessment of cell cycle alterations and unfolded protein response activation.

Main Results:

  • A novel synthetic lethal interaction was identified between PELO-HBS1L and SKI complexes.
  • SKI complex destabilization leads to dependence on the PELO-HBS1L ribosomal rescue complex in specific tumor types.
  • This synthetic lethality activates the unfolded protein response via IRE1 and inhibits tumor growth.

Conclusions:

  • PELO and HBS1L are potential novel therapeutic targets in cancer.
  • SKI complex destabilization serves as a biomarker for this synthetic lethality.
  • This approach targets a significant patient population across diverse genetic contexts.

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