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.
Uncontrolled progression through the cell cycle sustains the growth and progression of cancer. The cell cycle is comprised of 4 phases that are tightly regulated by two key transcriptional modulators, RB-E2F and MUVB complexes that regulate gene expression during the G1/S and G2/M cell cycle transitions, respectively. Target transcriptomes of both complexes overlap, suggesting that maximal inhibition of cell cycle progression, requires targeting both. Inhibitors that regulate the RB-E2F signaling axis have been FDA approved for treatment of a subset of breast cancers. These drugs specifically inhibit two kinases involved in the cell cycle known as CDK4 and CDK6. Palbociclib and abemaciclib, CDK4/CDK6 inhibitors (CDK4/6i), decrease cell proliferation by inducing a G1 cell cycle arrest. In contrast to CDK4/6, we previously reported that the activity of MUVB complex can be repressed using inhibitors of BET proteins, including the tool compound, JQ1. We hypothesized that dual targeting of MUVB and CDK4/CDK6 will synergize in breast cancer models to further decrease growth. To test this hypothesis, we assessed the impact of growth by adding JQ-1 to CDK4/6i in multiple intrinsically resistant cell lines. We found that addition of JQ-1 reduced IC50 of CDK4/6i by 60-75% and that the combination displayed synergistic growth suppression. Mechanistically, analysis of mRNA and protein expression revealed that the combination had greater ability to suppress expression of proteins that are MUVB target genes, G2/M, compared to single agents. We found through genetic and pharmacological approaches that inhibition of G2/M proteins Aurora Kinase A and NEK2 mediated CDK4/6i inhibitor response. Preclinical xenograft models confirmed that combined inhibition of CDK4/6 and MUVB, NEK2, or Aurora Kinase A can synergistically suppress tumor growth. Together, these results indicate that dual targeting of distinct phases of the cell cycle should be a more efficacious approach for suppressing breast cancer growth and provide a potential approach for blocking the acquisition of resistance to CDK4/6 inhibitors, a major clinical challenge for the treatment of luminal breast cancer. Citation Format: Leslie Cuellar-Vite, Kristen Weber-Bonk, Ruth A. Keri. Targeting the MUVB complex or downstream G2/M proteins potentiates CDK4/6 inhibitor efficacy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2301.
Triple negative breast cancer (TNBC) is a collection of heterogeneous diseases with limited therapeutic options primarily involving cytotoxic chemotherapy. The distinct molecular profile and increased chromosomal instability (CIN) of TNBC make it a difficult disease to treat. While many patients initially respond to treatment, resistance is common, resulting in poor patient outcomes. Thus identifying vulnerabilities in this disease is necessary to improve TNBC patient outcomes. To identify potential therapeutic targets in this disease, we focused on Src Family Kinases (SFKs). The SFK family is comprised of 9 non-receptor tyrosine kinases that interact with upstream signaling partners to regulate cell phenotypes such as adhesion, motility, survival and mitosis. Five SFKs are overexpressed in breast cancer, including Src, the founding member of the family. Within the basal breast cancer subtype, one of the most highly overexpressed SFKs is YES1. High YES1 expression is also associated with poorer outcomes in TNBC patients when compared to tumors with low YES1 expression. We have found that TNBC cells are reliant on sustained YES1 expression for viability, growth, cell cycle progression, and maintenance of genomic stability. Transiently silencing YES1 causes a significant decrease in cell growth and increase in apoptosis. Furthermore, loss of YES1 expression induces features of whole chromosomal instability (w-CIN), including micronucleation, multinucleation, and dysmorphic nuclei. An increase in γ-H2AX positive staining was also noted in cells with decreased YES1 expression, indicating an accumulation of double strand DNA breaks (DSB) that are indicative of structural chromosomal instability (s-CIN). These findings were recapitulated using several pan-SFK inhibitors, including FDA approved agents dasatinib and saracatinib. Loss of YES1 function also results in perturbed cell cycle progression, particularly a G2/M delay. RNA-sequencing and Reverse Phase Protein Array (RPPA) revealed alterations in mitotic, replication stress, and DNA repair pathways following the loss of YES1. These data demonstrate that YES1 is a previously understudied signaling component of mitotic- and DNA damage-regulating pathways in TNBC. More broadly, they suggest that YES1 may be a therapeutically targetable vulnerability that could be paired with other DNA damaging or mitotic inhibitors to improve treatment efficacy in TNBC. Current SFK-targeted agents globally impact all SFKs. The data presented here support efforts to identify a YES1 selective inhibitor that should be more specific for treating TNBC with less toxicity that pan-SFK drugs. Citation Format: Katrina Piemonte, Elyse Donaubauer, Ruth Keri. The SRC family kinase, YES1, controls chromosomal stability and promotes growth of triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-06.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.