MYC inhibition by Omomyc causes DNA damage and overcomes PARPi resistance in breast cancer
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 only direct MYC inhibitor that has completed a phase 1 trial, shuts down DDR genes in triple-negative breast cancer (TNBC), causing DDR defects and inducing DNA damage. Since DDR-deficient tumors are currently targeted by poly ADP-ribose polymerase inhibitors (PARPis), we tested combinations with Omomyc. We show that Omomyc-induced DNA damage is enhanced by PARPis 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 PARPis in PARPi-resistant TNBC, where MYC transcriptional activity represents a predictive biomarker of resistance to therapy.
Authors
- Virginia Castillo Cano (ORCID: https://orcid.org/0000-0002-0671-4632)
- Marie-Ève Beaulieu (ORCID: https://orcid.org/0000-0001-5224-8436)
- Olga Rodríguez (ORCID: https://orcid.org/0000-0003-0511-5176)
- Violeta Serra
- Fara Brasó‐Maristany (ORCID: https://orcid.org/0000-0001-5440-9643)
- Erika Serrano
- Magdalena Arnal (ORCID: https://orcid.org/0000-0001-8647-9232)
- Mariano F. Zacarías Fluck (ORCID: https://orcid.org/0000-0002-7171-4268)
- A. Rodríguez (ORCID: https://orcid.org/0000-0002-4899-6607)
- Judit Grueso (ORCID: https://orcid.org/0000-0003-1093-7940)
- Íñigo González-Larreategui (ORCID: https://orcid.org/0000-0002-0959-8497)
- Flaminia Pedretti (ORCID: https://orcid.org/0009-0002-4855-6078)
- Laia Foradada (ORCID: https://orcid.org/0000-0002-0589-4360)
- Laura Soucek (ORCID: https://orcid.org/0000-0002-4750-7971)
- Lara Nonell (ORCID: https://orcid.org/0000-0002-8538-8213)
- Jonathan R. Whitfield (ORCID: https://orcid.org/0000-0002-4925-7283)
- Alba Llop‐Guevara (ORCID: https://orcid.org/0000-0002-7913-9472)
- Fabio Giuntini
- Sílvia Casacuberta‐Serra (ORCID: https://orcid.org/0000-0002-2595-1115)
- Sergio López‐Estévez (ORCID: https://orcid.org/0000-0001-5355-8073)
- Sandra Martínez-Martín
- Andrea Herencia-Ropero (ORCID: https://orcid.org/0000-0002-1699-0251)
- Judith Balmañà (ORCID: https://orcid.org/0000-0002-0762-6415)
- Marta Guzmán (ORCID: https://orcid.org/0000-0002-0924-9887)
- Hugo Thabussot
- Daniel Massó-Vallés (ORCID: https://orcid.org/0000-0003-4231-0456)
- Aleix Prat
Institutions
- Hebron University (PS)
- Vall d'Hebron Institut de Recerca (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Vall d'Hebron Institute of Oncology (ES)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1016/j.celrep.2025.116604
- Citations
- 3
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- Fundación Cellex
- European Commission
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación
- Horizon 2020 Framework Programme
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III