Abstract 6386: Omomyc synergizes with PARP inhibition (PARPi) and reverts resistance to therapy in multiple PARPi-resistant triple-negative breast cancer models

Abstract Background: Triple-negative breast cancer (TNBC) represents 15-20% of breast cancers and, despite several advances in treatment options, surgery, radio- and cytotoxic chemotherapy remain the standard of care. A specific subtype of TNBC bearing BRCA1 and/or BRCA2 mutation is currently treated in the clinic with PARP inhibition (PARPi). Unfortunately, this subtype represents only a minority of TNBC patients, and, within this group, many develop resistance. The MYC oncogene is amplified or deregulated in most cancer types, including TNBC. In our laboratory, we developed Omomyc, a MYC dominant negative that has shown potent antitumor activity in multiple cancer models and has successfully completed a Phase I clinical trial. We recently demonstrated that the Omomyc mini-protein is an effective therapy in metastatic breast cancer models. Methods: RNA sequencing and immunoblotting were used to assess the potent effect of Omomyc on MYC transcriptional activity and on DNA damage response (DDR) pathways in a panel of PARPi-resistant TNBC cell lines. Subsequently, proliferation and synergy assays were performed combining Omomyc with either Olaparib or Talazoparib in vitro in the same panel of cells. Then, cell-derived xenografts (CDXs) and a cohort of TNBC patient-derived xenografts (PDXs) resistant to PARPi were also tested with this powerful combination in vivo. Results: We found that MYC inhibition (MYCi) by Omomyc shuts down genes and gene-sets related to the homologous recombination repair (HRR) pathway in TNBC, independently of the mutational profile. Indeed, we showed that MYCi causes HRR deficiency in both PARPi-resistant BRCA wild-type and BRCA-mutated cell lines, by depleting both PARP1 and RAD51, among other DDR proteins. Importantly, we observed synergistic responses of Omomyc combined with PARPi, both in vitro, through synergy matrices, and in vivo, in CDXs models, where not only the response to therapy was improved by the combination as compared to monotherapies, but also synergistic responses were seen in terms of BOR after only one week of treatment. Lastly, we confirmed these results within a cohort of PDXs resistant to PARPi, in which Omomyc was able to potently re-sensitize these clinically relevant models to therapy. Conclusions: Taken together, our findings suggest that Omomyc can be used in the context of PARPi-resistant TNBC. Indeed, our research shows that combining MYCi with PARPi would be an effective therapy, not only in BRCA-mutated tumors, but in potentially all TNBC patients, including those that have developed resistance to PARPi. Citation Format: Fabio Giuntini, Andrea Herencia-Ropero, Íñigo González-Larreategui, Silvia Casacuberta-Serra, Sandra Martínez-Martín, Mariano F. Zacarías-Fluck, Hugo Thabussot, Laia Foradada, Erika Serrano, Judit Grueso, Sergio López-Estévez, Flaminia Pedretti, Olga Rodríguez, Marta Guzmán, Marie-Eve Beaulieu, Lara Nonell, Violeta Serra, Jonathan Richard Whitfield, Daniel Massó-Vallés, Laura Soucek. Omomyc synergizes with PARP inhibition (PARPi) and reverts resistance to therapy in multiple PARPi-resistant triple-negative breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6386.