XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells
Tao Zou,
Meng Zhou,
Akansha Gupta,
Patrick Zhuang,
Alyssa R. Fishbein,
Hope Y. Wei,
Diego Capcha-Rodriguez,
Zhouwei Zhang,
Andrew D. Cherniack,
Matthew Meyerson
Affiliations
Tao Zou
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Meng Zhou
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Akansha Gupta
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Patrick Zhuang
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Alyssa R. Fishbein
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Hope Y. Wei
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Diego Capcha-Rodriguez
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Zhouwei Zhang
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Andrew D. Cherniack
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Matthew Meyerson
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Corresponding author
Summary: Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene expression. XRN1 deletion causes PKR pathway activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and how this interaction creates a vulnerability in cancer cells with an activated interferon cell state.
