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bioRxiv · 10.64898/2026.07.06.736708

Viral rewiring of DDR signaling activates a pro-survival network that drives chemotherapy resistance

Kong, J.·Azhar, H. M. F.·Akmel, A.·Wen, F.·Xu, J.·Thomas, M. A.
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Abstract

Radiation and chemotherapy rely on an intact DNA damage response (DDR) to halt cell-cycle progression and eliminate damaged cells, yet many tumors evade these outcomes and develop resistance. Adenoviruses remodel host signaling networks in ways that mirror tumor evolution, providing a powerful system to dissect how DDR pathways are subverted. Here, we identify two scenarios in which the central DDR kinases ATM and ATR are reprogrammed from enforcing CHK1/CHK2-dependent checkpoint arrest to activating a NEMO-NF-{kappa}B survival pathway. This rewiring induces transcriptional programs associated with stress tolerance, anti-apoptotic signaling, and chemoresistance, and promotes the accumulation of cells with abnormal DNA content. These findings reveal a previously unrecognized mode of DDR plasticity that generates a pro-survival state reminiscent of early tumor evolution and suggest how ATM- and ATR-dependent pathways can be co-opted to promote therapeutic resistance.

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Kong, J., Azhar, H. M. F., Akmel, A., Wen, F., Xu, J., Thomas, M. A.. 2026-07-08. Viral rewiring of DDR signaling activates a pro-survival network that drives chemotherapy resistance. https://doi.org/10.64898/2026.07.06.736708

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