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 first direct MYC inhibitor to pass a Phase 1 trial, shuts down DDR genes in triple-negative breast cancer (TNBC), causing DDR defects and inducing DNA damage. Since DDR-deficient tumours are currently targeted by PARP inhibitors (PARPi), we tested combinations with Omomyc. We show that Omomyc-induced DNA damage is enhanced by PARPi 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 PARPi in PARPi-resistant TNBC, where MYC transcriptional activity represents a predictive biomarker of resistance to therapy. Overall design: MDA-MB-231 cells were purchased from ATCC (catalogue no. HTB-26) and were maintained in DMEM/F12 (Life Technologies) with 10% FBS. MDA-MB-231 cells were treated with 30µM Omomyc and vehicle for 120 hours. Total RNA extraction of the cell-line samples was done by Qiagen RNeasy Mini Kit and quality checked by TapeStation. The extracted RNA was purified with oligo(dT) magnetic beads to capture mRNAs, fragmented and subject to a stranded RT proceeding with library preparation protocol from Illumina Stranded mRNA Prep. Library QC included fluorometric quantification (Qubit) and fragment size distribution (TapeStation). The prepared libraries were sequenced with Illumina NovaSeq.