Year: 2025
Type: article
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 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.
Source: Cell Reports
Authors: Fabio Giuntini, Íñigo González-Larreategui, Andrea Herencia-Ropero, Silvia Casacuberta-Serra, Mariano F. Zacarías-Fluck, Magdalena Arnal, Flaminia Pedretti, Sandra Martínez-Martín, Hugo Thabussot, Virginia Castillo Cano, Judit Grueso, Laia Foradada, Erika Serrano, Sergio López-Estévez, Olga Rodriguez, Marta Guzman, Adela Rodriguez-Hernandez, Fara Brasó-Maristany, Alba Llop-Guevara, Judith Balmaña, Lara Nonell, Aleix Prat, Violeta Serra, Marie-Eve Beaulieu, Jonathan R. Whitfield, Daniel Massó-Vallés, Laura Soucek
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Fundación Cellex, European Commission, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Ministerio de Ciencia e Innovación, Fundación Fero, Horizon 2020 Framework Programme, European Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, H2020 European Research Council
Awards: G1470396050, G1732275149, G2623550088, G2708797839, G3116040360, EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts, G3323679526, G3637993957, G4532900596, G4596467486, G4937468798, G5617133539, G5639348546, G6348690346, G7296665975, G7301267333, G8824911526
OpenAlex ID: W4416528713