Abstract 1487: MYC inhibition modulates DNA damage response and is capable of enhancing PARPi therapeutic impact

Abstract Background: The MYC oncogene, amplified or dysregulated in about 70% of human tumors, orchestrates multiple cancer hallmarks. Interestingly, its role in DNA damage response (DDR) has been debated for decades. On one hand, oncogenic MYC has been shown to promote genomic instability, while, on the other hand, it can also enhance DNA repair. We developed Omomyc, the first MYC dominant negative to have successfully completed a Phase I clinical trial, and used it as a research tool to study MYC’s role in DDR. We focused on TNBC, where defective DDR is clinically associated with the use of PARP inhibitors (PARPi). Methods: First, RNAseq, WB, immunofluorescence and flow cytometry were used to test Omomyc’s effect on DDR genes in a panel of TNBC cells and its direct contribution to DNA damage. In addition, proliferation, apoptosis and synergy assays were performed to test the combination of Omomyc and PARPi in vitro. Then, cell derived xenografts (CDXs) and patient-derived xenografts (PDXs) were treated with the combination in vivo. Furthermore, bulk RNAseq from 35 patient derived xenografts (PDXs) was performed to elucidate the role of MYC transcriptional activity in PARPi resistance. Lastly, digital spatial profiling (DSP) of 18 patients’ biopsies prior to PARPi treatment is being performed to evaluate if MYC transcriptional signature could be a predictor of patients’ response to PARPi. Results: We found that Omomyc shuts down genes and gene-sets related to homologous recombination repair (HRR) in both BRCA wild-type and PARPi-resistant BRCA-mutated cell lines, by depleting DDR proteins. Also, we observed that Omomyc causes early DNA damage, inducing phosphorylation of H2AX. Importantly, we found that the combination with PARPi, further increases H2AX phosphorylation, resulting in apoptosis in the long term, both in vitro and in vivo. RNAseq of 35 PARPi-treated PDXs showed that those resistant to PARPi therapy have a significantly increased MYC transcriptional activity, suggesting its role in drug resistance. At the time of submission of this abstract, DSP of 16 patients’ biopsies is being performed to evaluate if the MYC transcriptional signature can be used as a predictor for PARPi response. Conclusions: Overall, we show evidence that MYC inhibition by Omomyc phenocopies HR deficiency and induces DNA damage in TNBC. In addition, our research shows that combining Omomyc with PARPi would be an effective therapy in PARPi-resistant TNBC, where MYC transcriptional activity is over-represented and could potentially be a predictive biomarker of resistance to therapy. Citation Format: Fabio Giuntini, Andrea Herencia-Ropero, Íñigo González-Larreategui, Silvia Casacuberta-Serra, Sandra Martínez-Martín, Mariano F. Zacarías-Fluck, Hugo Thabussot, Flaminia Pedretti, Laia Foradada, Erika Serrano, Judit Grueso, Sergio López-Estévez, Olga Rodríguez, Marta Guzmán, Adela Rodríguez-Hernández, Fara Brasó-Maristany, Marie-Eve Beaulieu, Lara Nonell, Violeta Serra, Aleix Prat, Jonathan Richard Whitfield, Daniel Massó-Vallés, Laura Soucek. MYC inhibition modulates DNA damage response and is capable of enhancing PARPi therapeutic impact [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 1487.