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

GSE309250 Homo sapiens Expression profiling by high throughput sequencing 4 samples Submitted 2025/09/26 Platform GPL24676
Summary
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.
Published in
MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer
Giuntini F, González-Larreategui Í, Herencia-Ropero A et al. · Cell reports 2025 · PMID 41273720 · doi:10.1016/j.celrep.2025.116604
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Also filed as BioProject PRJNA1334427 and SRA study SRP627395. Searching any of these in the dataset finder brings you back here.

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