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

Triple negative breast cancer (TNBC) is a heterogeneous disease with limited therapeutic options. Two commonalities of TNBCs are a failure to express receptors for hormone or HER2-targeted therapies and high levels of chromosomal instability (CIN), both of which generate considerable therapeutic challenges. Focusing on the Src Family Kinases (SFKs), we found that treatment of TNBC cells with pan-SFK inhibitors causes abnormal nuclear phenotypes and DNA double strand breaks that are characteristic of excessive CIN, suggesting that SFKs may provide a vulnerability for treating TNBC. While prior clinical studies found that pan-SFK inhibition causes dose-limiting toxicities and minimal efficacy, we asked whether targeting individual family members may provide more specificity and hence, greater impact. Analysis of public datasets revealed that YES1 is one of the most highly expressed SFKs in basal/TNBC breast cancer and that its expression is associated with poor patient outcomes. Genomic and pharmacologic targeting of YES1 in TNBC cells further demonstrated that its sustained activity is essential for normal mitoses, including centrosome composition and bipolar spindle formation, as well as chromosome stability. We then determined if the ability of YES1 inhibition to induce mitotic defects and profound CIN could be leveraged to potentiate the efficacy of taxanes, cornerstone drugs for TNBC that also induce CIN. Combining paclitaxel with the selective YES1 inhibitor, CH695355, synergistically inhibited growth of several TNBC models both in vitro and in vivo. Moreover, YES1 inhibition re-sensitized taxane-resistant TNBC cells to paclitaxel. Elevated tumor expression of YES1 was also associated with worse overall survival of TNBC patients treated with combined taxanes/anthracyclines. Mechanistically, YES1 suppression leads to a loss of FOXM1 expression, a transcription factor whose disruption has also been reported to induce CIN, but has not yet been effectively therapeutically targeted. Together, these studies demonstrate that the SFK family member, YES1, is a novel and essential regulator of genome stability in TNBC. More broadly, these results suggest that YES1 may be a therapeutically targetable vulnerability that could potentiate the efficacy of mitotic inhibitors to induce maladaptive CIN and improve the treatment of TNBC.