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bioRxiv · 10.1101/2023.08.01.551488

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

Zou, T.·Zhou, M.·Gupta, A.·Zhuang, P.·Fishbein, A. R.·Wei, H. Y.·Zhang, Z.·Cherniack, A. D.·Meyerson, M.
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Abstract

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 (ISG) expression. XRN1 deletion causes PKR 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-{beta} 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 nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.

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Zou, T., Zhou, M., Gupta, A., Zhuang, P., Fishbein, A. R., Wei, H. Y., Zhang, Z., Cherniack, A. D., Meyerson, M.. 2023-08-03. XRN1 deletion induces PKR-dependent cell lethality in interferon-activated cancer cells. https://doi.org/10.1101/2023.08.01.551488

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