Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.

Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit antitumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple-negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multipolar spindles, and chromosomal instability. Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated chromosomal instability for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of patients with TNBC treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.  Significance: YES1 is a sentinel regulator of genomic maintenance that controls centrosome homeostasis and chromosome stability through FOXM1, revealing this pathway as a therapeutic vulnerability for enhancing taxane efficacy in triple-negative breast cancer.