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 MYC ^HIGH 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 MYC ^HIGH 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.