Abstract P1-13-11: YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Due to the lack of receptor expression, there are limited targeted therapies available for TNBC. As a result, TNBC patients are primarily treated with chemotherapies such as taxanes. Although TNBCs initially regress in response to taxane treatment, resistance is common. One mechanism of taxol unresponsiveness/resistance is an increase in chromosomal instability (CIN). Increased CIN can confer survival advantages to cancer cells and increase their aggressiveness. However, CIN levels can be leveraged using drugs that inhibit proteins important for chromosomal stability. Combining CIN-inducing drugs, such as taxanes, can improve treatment efficacy or re-sensitize tumor cells to certain drugs by shifting cells towards a state of maladaptive CIN that is incompatible with cell viability. We have found that the non-receptor SRC family kinase YES1 is crucial for chromosomal stability. YES1 is important for cell division, motility, adhesion, and survival in both normal and TNBC cells. Since taxol and YES1 silencing independently increase chromosomal instability, I hypothesized that combining a YES1 inhibitor (YES1i) with taxanes would shift cells toward an irreversible state of maladaptive CIN, decreasing their survival. I found that YES1 mRNA and protein are upregulated in taxane-resistant cells and that YES1 protein expression correlates with the paclitaxel IC50 in a panel of TNBC cell lines, suggesting that YES1 may drive taxane resistance. Furthermore, I found that a selective YES1 inhibitor (CH6953755) synergizes with paclitaxel and improves taxane response in both in vitro and in vivo TNBC models. In addition, the combination of YES1i and paclitaxel treatment increases phenotypes associated with chromosomal instability more than either drug alone. These data suggest that YES1 inhibition in combination with taxanes represents an innovative and novel drug treatment regimen that improves TNBC patient outcomes. Citation Format: Natasha Ingles, Katrina Piemonte, Salendra Singh, Kristen Weber-Bonk, Ruth Keri. YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-11.