Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer
Amir Hosseini,
Håvard T. Lindholm,
Raymond Chen,
Parinaz Mehdipour,
Sajid A. Marhon,
Charles A. Ishak,
Paul C. Moore,
Marie Classon,
Andrea Di Gioacchino,
Benjamin Greenbaum,
Daniel D. De Carvalho
Affiliations
Amir Hosseini
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
Håvard T. Lindholm
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pathology, Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway
Raymond Chen
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
Parinaz Mehdipour
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7DQ, UK
Sajid A. Marhon
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Charles A. Ishak
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
Paul C. Moore
Pfizer Centers for Therapeutic Innovation, South San Francisco, CA 94080, USA
Marie Classon
Pfizer Centers for Therapeutic Innovation, South San Francisco, CA 94080, USA
Andrea Di Gioacchino
Laboratoire de Physique de l’Ecole Normale Supérieure, PSL & CNRS UMR8063, Sorbonne Université, Université de Paris, Paris, France
Benjamin Greenbaum
Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Daniel D. De Carvalho
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Corresponding author
Summary: Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune responses. Here, we systematically identify mechanisms of viral mimicry adaptation associated with cancer cell dependencies. Among the top hits is the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1 dependency is mediated by mitochondrial antiviral signaling protein and protein kinase R activation and is associated with higher levels of cytosolic dsRNA, higher levels of a subset of Alus capable of forming dsRNA, and higher interferon-stimulated gene expression, indicating that cells die due to induction of viral mimicry. Furthermore, dsRNA-inducing drugs such as 5-aza-2′-deoxycytidine and palbociclib can generate a synthetic dependency on XRN1 in cells initially resistant to XRN1 knockout. These results indicate that XRN1 is a promising target for future cancer therapeutics.
