Cancer letters · 2026
DNA-PKcs promotes therapy resistance and metastatic recurrence in neuroblastoma.
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Norouzi Mahnaz, Kim Subin, Zhu Beibei, Wang Chi, Wu Natalie, Somers Katherine, Yang Eddy Shih-Hsin, Mark Evers B, Rellinger Eric J, Rychahou Piotr
Аннотация
PURPOSE: High-risk neuroblastoma presents a serious clinical challenge with survival rates below 50%. Disease relapse most commonly occurs at distant metastatic sites and remains the primary driver of poor outcomes, emphasizing the need for therapies to target drivers of relapse.
EXPERIMENTAL DESIGN: This study identified DNA-PKcs as a critical determinant of poor survival and metastatic relapse in neuroblastoma patients. We evaluated which therapeutic modality-chemotherapy or radiotherapy-when combined with DNA-PKcs inhibition, more effectively reduces metastatic burden and prevents recurrence.
RESULTS: Colony-forming assays revealed that established neuroblastoma colonies resist doxorubicin alone and require high-dose doxorubicin paired with DNA-PKcs inhibition to suppress progression. In contrast, low-dose radiotherapy in combination with DNA-PKcs inhibition effectively controlled colony progression. Maximal synergy between radiotherapy and DNA-PKcs inhibition was achieved when the inhibitor was administered within 4 h post-irradiation. Chronic co-exposure to doxorubicin and peposertib encouraged emergence of therapy-resistant cells, whereas chronic co-exposure to radiotherapy combined with peposertib disrupted neuroblastoma cells self-renewal and prevented long-term colony maintenance. In neuroblastoma metastases, adding DNA-PKcs inhibition to doxorubicin improved efficacy but induced gastrointestinal side effects and failed to eradicate tumors; pairing it with low-dose, fractionated radiotherapy resulted in total lesion regression, impaired tumor self-renewal, and prevented systemic adverse effects.
CONCLUSIONS: Our findings correlate elevated DNA-PKcs levels with poor patient prognosis and show that low-dose radiotherapy combined with peposertib effectively abrogates neuroblastoma self-renewal compared to chemotherapy-based regimens, thereby implicating DNA-PKcs as a key mediator of metastatic relapse and supporting radiotherapy plus DNA-PKcs inhibition as a compelling therapeutic strategy for relapsed or refractory high-risk neuroblastoma.
EXPERIMENTAL DESIGN: This study identified DNA-PKcs as a critical determinant of poor survival and metastatic relapse in neuroblastoma patients. We evaluated which therapeutic modality-chemotherapy or radiotherapy-when combined with DNA-PKcs inhibition, more effectively reduces metastatic burden and prevents recurrence.
RESULTS: Colony-forming assays revealed that established neuroblastoma colonies resist doxorubicin alone and require high-dose doxorubicin paired with DNA-PKcs inhibition to suppress progression. In contrast, low-dose radiotherapy in combination with DNA-PKcs inhibition effectively controlled colony progression. Maximal synergy between radiotherapy and DNA-PKcs inhibition was achieved when the inhibitor was administered within 4 h post-irradiation. Chronic co-exposure to doxorubicin and peposertib encouraged emergence of therapy-resistant cells, whereas chronic co-exposure to radiotherapy combined with peposertib disrupted neuroblastoma cells self-renewal and prevented long-term colony maintenance. In neuroblastoma metastases, adding DNA-PKcs inhibition to doxorubicin improved efficacy but induced gastrointestinal side effects and failed to eradicate tumors; pairing it with low-dose, fractionated radiotherapy resulted in total lesion regression, impaired tumor self-renewal, and prevented systemic adverse effects.
CONCLUSIONS: Our findings correlate elevated DNA-PKcs levels with poor patient prognosis and show that low-dose radiotherapy combined with peposertib effectively abrogates neuroblastoma self-renewal compared to chemotherapy-based regimens, thereby implicating DNA-PKcs as a key mediator of metastatic relapse and supporting radiotherapy plus DNA-PKcs inhibition as a compelling therapeutic strategy for relapsed or refractory high-risk neuroblastoma.