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ATR inhibition synergizes with alkylating PI polyamide targeting MYCN by suppressing DNA repair in MYCN-amplified neuroblastoma

ABSTRACT: Because a single treatment with CCC-002 downregulated the expression of DDR-related genes in CHP-134 cells, the expression profile of SK-N-BE(2) cells after co-treatment with CCC-002 and an ATR inhibitor was evaluated using a microarray assay

ORGANISM(S): Homo sapiens

PROVIDER: GSE285823 | GEO | 2025/01/31

REPOSITORIES: GEO

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ATR inhibition synergizes with alkylating PI polyamide targeting MYCN by suppressing DNA repair in MYCN-amplified neuroblastoma

Project description:ATR inhibition synergizes with alkylating PI polyamide targeting MYCN by suppressing DNA repair in MYCN-amplified neuroblastoma

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H3K27ac, H3K4me and H3K4me3 binding examined by ChIP-seq in the CHP-134 neuroblastoma cell line

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Project description:Amplification of MYCN plays a pivotal role in multiple types of tumors and correlates with poor prognosis in high-risk neuroblastoma. Despite recent advances in the treatment of neuroblastoma, no approaches directly target the master oncogene MYCN. Difficulties in targeting the MYCN protein have inspired us to develop a new gene level inhibitory strategy using a sequence-specific gene regulator. Here we generated a MYCN-targeting pyrrole-imidazole (PI) polyamide, MYCN-A3, which directly binds to and alkylates DNA at homing motifs within MYCN transcript. Pharmacological suppression of MYCN inhibited the proliferation of cancer cells harboring MYCN amplification compared with MYCN non-amplified cancer cells. In neuroblastoma xenograft mouse models, MYCN-A3 specifically downregulated MYCN expression and suppressed tumor progression with no detectable adverse effects and resulted in prolonged overall survival. Moreover, we observed the copy number reduction of MYCN in neuroblastoma cells with MYCN amplification upon treatment with MYCN-A3 but not MYCN non-targeting PI polyamide. Expression microarray experiments were also performed to compare the genome-wide effect of MYCN-A3 with CRISPR/Cas9 silencing of MYCN (MYCNcr-a).

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