Fabio Giuntini, Íñigo González-Larreategui, Andrea Herencia-Ropero, Sílvia 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 Rodríguez, Marta Guzmán, A. Rodríguez, Fara Brasó‐Maristany, Alba Llop‐Guevara, Judith Balmañà, Lara Nonell, Aleix Prat, Violeta Serra, Marie-Ève Beaulieu, Jonathan R. Whitfield, Daniel Massó-Vallés, Laura Soucek
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.