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.