MYC Overexpression Confers Sensitivity to TACC3 Inhibition for Triple-Negative Breast Cancer

The oncogenic transcription factor MYC is overexpressed across many cancer types, including triple-negative breast cancers (TNBCs), where it drives cell proliferation, chromosomal instability, and immune suppression. As MYC has proven difficult to target directly, identifying vulnerabilities created by MYC-driven mitotic rewiring is of significant therapeutic interest. Using a focused pharmacological screen of mitosis-related targets that are overexpressed in the context of MYC signaling, we identified several previously unrecognized dependencies on mitotic spindle proteins, including KIF18A and TACC3 in MYCHIGH cells. We focused on TACC3 and found the small molecule inhibitor BO-264 induced pronounced micronuclei formation, cell cycle arrest, transcriptional reactivation of inflammatory signaling, and heightened cytotoxicity in MYCHIGH models. TACC3 inhibition activates interferon-stimulated response element (ISRE) mediated inflammatory signaling and can activate the cGAS-STING pathway in a subset of triple-negative breast cancer contexts. Together, these findings identify TACC3 as a MYC-driven mitotic vulnerability. We highlight TACC3 inhibition as a promising strategy to impair tumor cell fitness and activate tumor-intrinsic inflammatory responses in MYC-driven cancers.