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

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

PROVIDER: PRJNA1206146 | ENA |

REPOSITORIES: ENA

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

Project description: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

2025-01-31 | GSE285823 | GEO

Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide in Neuroblastoma Cells (CHP-134)

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).

2018-12-25 | GSE121528 | GEO

Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide in Neuroblastoma Cells (CHP-134)

Project description:Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide in Neuroblastoma Cells (CHP-134)

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Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (LS180)

Project description:Pyrrole-imidazole polyamides are versatile DNA minor groove binders and attractive therapeutic options against oncological targets, especially upon functionalization with an alkylating agent such as endo-seco-CBI. These molecules also provide an alternative for oncogenes deemed “undruggable” at the protein level, where the absence of solvent-accessible pockets or structural crevices prevent the formation of protein-inhibitor ligands; nevertheless, the genome-wide effect of pyrrole-imidazole polyamide binding remain largely unclear to-date. Here we propose a next-generation sequencing-based workflow combined with whole genome expression arrays to address such issue using a candidate anti-cancer alkylating agent, KR12, against codon 12 mutant KRAS. Biotinylating KR12 enables the means to identify its genome-wide effects in living cells and possible biological implications via a coupled workflow of enrichment-based sequencing and expression microarrays. The subsequent computational pathway and expression analyses allow the identification of its genomic binding sites, as well as a route to explore a polyamide’s possible genome-wide effects. Among the 3,343 KR12 binding sites identified in the human LS180 colorectal cancer genome, the reduction of KR12-bound gene expressions was also observed. Additionally, the coupled microarray-sequencing analysis also revealed some insights about the effect of local chromatin structure on pyrrole-imidazole polyamide, which had not been fully understood to-date. A comparative analysis with KR12 in a different human colorectal cancer genome SW480 also showed agreeable agreements of KR12 binding affecting gene expressions. Combination of these analyses thus suggested the possibility of applying this approach to other pyrrole-imidazole polyamides to reveal further biological details about the effect of polyamide binding in a genome.

2016-11-01 | GSE86597 | GEO

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes (SW480)

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RNA-seq of neuroblastoma mouse model (Alk-F1178S;Th-MYCN) after treatment with the ATR inhibitor ceralasertib

Project description:To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed 3 days after treatment of a previously developed neuroblastoma mouse model (Alk-F1178S;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor ceralasertib.

2023-11-30 | E-MTAB-12961 | biostudies-arrayexpress

Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

Project description:Alkylating pyrrole-imidazole polyamide KR12 binding in colorectal cancer genomes

| PRJNA342329 | ENA

Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide and CRISPR/Cas9 in Neuroblastoma Cells (CHP-134)

Project description:Direct Targeting of MYCN Gene Amplification by Alkylating Pyrrole-Imidazole Polyamide and CRISPR/Cas9 in Neuroblastoma Cells (CHP-134)

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LMO1 Synergizes with MYCN to Promotes Neuroblastoma Initiation and Metastasis

Project description:High levels of LMO1 expression synergizes with MYCN to accelerate neuroblastomagenesis, enhance disease penetrance and promote widespread metastasis in zebrafish. Transcriptomic analysis of human neuroblasotma cells with programed expression of LMO1 vs vector control or neuroblastoma cells with differential endogenous LMO1 expression revealed that gene signitures affecting tumor cell-extracellular matrix interaction are significantly associated with high levels of LMO1 expression. Our findings provide compelling evidence for a major pathogenic role of LMO1 in MYCN-driven neuroblastoma.

2017-07-31 | GSE90087 | GEO

RNA-seq of neuroblastoma mice models after treatment with the ATR inhibitor BAY 1895344

Project description:To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed after treatment of 2 previously developed neuroblastoma mouse models (Alk-F1178S;Th-MYCN and Rosa26_Alkal2;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor BAY 1895344.

2021-10-21 | E-MTAB-10616 | biostudies-arrayexpress

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