期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms24109012
关键词
neuroblastoma; MYCN; DNA-PK; DNA ligase 4
Identifying the vulnerability of altered DNA repair machinery that displays synthetic lethality with MYCN amplification is a therapeutic rationale in unfavourable neuroblastoma. However, none of the inhibitors for DNA repair proteins are established as standard therapy in neuroblastoma. DNA-PK inhibitor (DNA-PKi) showed inhibitory effects on the proliferation of MYCN-driven neuroblastoma spheroids and cell lines. Among them, DNA ligase 4 (LIG4) was identified as a prognostic factor and its inhibition combined with DNA-PKi may overcome resistance to multimodal therapy in MYCN-amplified neuroblastoma.
Identifying the vulnerability of altered DNA repair machinery that displays synthetic lethality with MYCN amplification is a therapeutic rationale in unfavourable neuroblastoma. However, none of the inhibitors for DNA repair proteins are established as standard therapy in neuroblastoma. Here, we investigated whether DNA-PK inhibitor (DNA-PKi) could inhibit the proliferation of spheroids derived from neuroblastomas of MYCN transgenic mice and MYCN-amplified neuroblastoma cell lines. DNA-PKi exhibited an inhibitory effect on the proliferation of MYCN-driven neuroblastoma spheroids, whereas variable sensitivity was observed in those cell lines. Among them, the accelerated proliferation of IMR32 cells was dependent on DNA ligase 4 (LIG4), which comprises the canonical non-homologous end-joining pathway of DNA repair. Notably, LIG4 was identified as one of the worst prognostic factors in patients with MYCN-amplified neuroblastomas. It may play complementary roles in DNA-PK deficiency, suggesting the therapeutic potential of LIG4 inhibition in combination with DNA-PKi for MYCN-amplified neuroblastomas to overcome resistance to multimodal therapy.
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