ABSTRACT: Triple negative breast cancer (TNBC) is a collection of heterogeneous disease with limited therapeutic options. One commonality of TNBCs is their distinct molecular profiles and increased chromosomal instability (CIN), both of which contribute to its difficulty to treat, but also offer points of leverage for therapeutic intervention. To capitalize on this vulnerability, we focused on Src Family Kinases (SFKs), a group comprised of 9-11 non-receptor tyrosine kinases that interact with upstream signaling partners to regulate cell phenotypes such as adhesion, motility, survival, and mitosis. We found that treatment with pan-SFK inhibitors leads to abnormal nuclear phenotypes and DNA double strand breaks, both characteristics of CIN, in TNBC cell lines. However, previous clinical studies demonstrated that pan-SFK inhibition resulted in significant toxicities and minimal efficacy in TNBC patients. Therefore, we sought to identify which, if any, of the SFK members may be a specific vulnerability in TNBC that was essential for maintenance of genomic integrity, mitotic progression, and cell survival. The SFK, YES1, was identified to be one of the most highly expressed SFKs in basal breast cancer, with high YES1 expression being correlated with poor patient outcomes. Using genomic depletion and pharmacologic inhibition, we demonstrated that sustained YES1 activity was essential for bipolar spindle formation, regulation of centrosome number, and maintenance of chromosomal stability. Combination treatment utilizing CIN-inducing therapies have been considered to improve treatment efficacy or re-sensitize tumor cells to certain drugs by inducing profound mitotic defects, maladaptive CIN, and cell death. Thus, we evaluated YES1 inhibition in combination with Taxols as an innovative drug treatment regimen that improves TNBC patient outcomes. We found that paclitaxel and the selective YES1 inhibitor, CH695355, synergized in both in vitro and in vivo TNBC models. Moreover, use of this inhibitor re-sensitized Taxol resistant TNBC cells to paclitaxel, a common obstacle in TNBC treatment. Our studies demonstrate that YES1 is a previously understudied component of genomic stability-regulating pathways in TNBC. More broadly, our data suggests that YES1 may be a therapeutically targetable vulnerability with the ability to be paired with other DNA damaging or mitotic inhibitors to improve treatment efficacy in TNBC.
