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MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer.

ABSTRACT: MYC is dysregulated in most human cancers and is a DNA damage response (DDR) modulator capable of both promoting genomic instability and enhancing DNA repair. Here, we show that Omomyc, the first direct MYC inhibitor to pass a Phase 1 trial, shuts down DDR genes in triple-negative breast cancer (TNBC), causing DDR defects and inducing DNA damage. Since DDR-deficient tumours are currently targeted by PARP inhibitors (PARPi), we tested combinations with Omomyc. We show that Omomyc-induced DNA damage is enhanced by PARPi and that the inhibitors cooperate even in models with intrinsic or acquired PARPi resistance, both in vitro and in vivo. Moreover, using patient-derived models and clinical samples, we reveal a role for MYC as a predictor of PARPi resistance. Overall, our research highlights the opportunity of combining MYC inhibition by Omomyc with PARPi in PARPi-resistant TNBC, where MYC transcriptional activity represents a predictive biomarker of resistance to therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309250 | GEO | 2025/09/26

REPOSITORIES: GEO

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MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer.

Project description:MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer.

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Transient splicing inhibition causes persistent DNA damage and enhances chemotherapy vulnerability in homologous recombination proficient triple-negative breast cancer

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Project description:MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programs but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc – a MYC derived polypeptide interfering with MYC activity – taking as model the most lethal brain tumor, glioblastoma. Omomyc bridles the key cancer stem-like cell features and affects tumor microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper Myc localization and binds to DNA, with a preference for sites previously occupied by MYC. This is accompanied by (leads to) selective repression of master transcription factors for glioblastoma stem-like cell identity like POU3F2, SOX2, and OLIG2, upregulation of effectors of tumor suppression and differentiation such as PTEN, ID4, MIAT, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion like EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of the gene expression programs controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.

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2010-12-21 | E-GEOD-25039 | biostudies-arrayexpress

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Project description:Purpose: Identify MYC sensitive enes that are affected by treatment with Omomyc

2019-09-01 | GSE131075 | GEO

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Project description:MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programs but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc – a MYC derived polypeptide interfering with MYC activity – taking as model the most lethal brain tumour, glioblastoma. Omomyc bridles the key cancer stem-like cell features and affects tumour microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper Myc localisation and binds to DNA, with a preference for sites previously occupied by MYC. This is accompanied by (leads to) selective repression of master transcription factors for glioblastoma stem-like cell identity like POU3F2, SOX2, and OLIG2, upregulation of effectors of tumour suppression and differentiation such as PTEN, ID4, MIAT, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion like EGFR and ZEB1. Data support a novel view of MYC as a network stabiliser that strengthens the regulatory nodes of the gene expression programs controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.

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