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XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells

Tao Zou1, Meng Zhou1, Akansha Gupta1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Cell Reports
|January 23, 2024
PubMed

Insights

Deleting the exoribonuclease XRN1 activates the protein kinase R (PKR) pathway, leading to cancer cell death. This highlights a new therapeutic strategy targeting viral mimicry in cancer treatment.

Area of Science:

  • Oncology
  • Virology
  • Immunology

Background:

  • Inducing viral mimicry via double-stranded RNA (dsRNA) sensors is a potential cancer therapy.
  • Targeting regulators of dsRNA sensing pathways can induce this response.

Purpose of the Study:

  • To investigate the role of exoribonuclease XRN1 in regulating dsRNA sensing pathways in cancer cells.
  • To explore the therapeutic potential of targeting XRN1 for cancer treatment.

Main Methods:

  • XRN1 deletion in cancer cells.
  • Assessing protein kinase R (PKR) pathway activation.
  • Evaluating cancer cell viability.
  • Modulating interferon signaling using ruxolitinib and interferon-β stimulation.

Main Results:

  • XRN1 deletion activates the PKR pathway, causing cancer cell lethality.
  • Disrupting interferon signaling with ruxolitinib rescues sensitivity to XRN1 deletion.
  • Interferon-β stimulation increases PKR levels and sensitivity to XRN1 inactivation.
  • XRN1 deletion leads to accumulation of endogenous complementary sense/anti-sense RNAs.

Conclusions:

  • XRN1 negatively regulates PKR in cancer cells with high interferon-stimulated gene expression.
  • XRN1 inactivation creates a vulnerability in cancer cells with an activated interferon state.
  • Targeting XRN1 represents a novel therapeutic strategy for cancers exhibiting an activated interferon signature.
Keywords:
CP: CancerCP: ImmunologyPKRRNA sensingXRN1cancerinterferon

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