SRC Family Kinases (SFKs) are a group of 9 non-receptor tyrosine kinases that mediate the effects of many extracellular and intracellular signaling pathways. While these proteins have often been considered to be functionally similar to SRC, the founding member of the family, it is now clear that they have non-redundant and unique activities. In cancer, these proteins are differentially expressed and their roles can even be antagonistic. This project launches from our discovery that one of these family members, YES1, is selectively overexpressed in Triple Negative Breast Cancer (TNBC), is associated with poor outcomes, and is necessary for sustained growth of TNBC cells. TNBC is a collection of highly aggressive diseases with limited therapeutic options primarily involving cytotoxic chemotherapy. While many patients initially respond to these treatments, resistance is common, resulting in poor patient outcomes. Thus, identifying vulnerabilities in this group of diseases is essential to yield approaches for improving survivorship. We propose that YES1 is one of these vulnerabilities. In preliminary data, we show that YES1 is essential for maintaining expression of Epidermal Growth Factor Receptor (EGFR) as well as ensuring mitotic fidelity. EGFR is a major driver of TNBC growth. When YES1 is depleted, EGFR is degraded and its signaling is lost. In addition, we report that YES1 silencing causes several nuclear defects including micro-, multi-, and dysmorphic nuclei indicating that YES1 is essential for accurate completion of mitosis. We hypothesize that these two functions of YES1 are essential for cellular viability in TNBC. Moreover, we propose that YES1 may be a useful therapeutic target to improve the efficacy of drugs targeting EGFR and mitosis.
In Aim 1, we will determine how YES1 controls EGFR degradation and assess whether YES1 overexpression underlies resistance to EGFR inhibitors in TNBC.
Aim 2 will focus on identifying specific events in mitosis that are impacted by YES1 and the mechanisms involved. It will also discern whether modulating YES1 can impact response to taxanes, mainstay chemotherapies for TNBC. Lastly, in Aim 3, we will determine if EGFR and YES1 participate in a feedforward loop that controls mitosis. This will involve interrogating the role of EGFR in mediating the effects of YES1 on mitosis and determining if EGFR is also an upstream regulator of YES1. Major innovations of this project include the identification of YES1 as a new oncogenic driver of TNBC, the discovery that YES1 and EGFR may control the genomic complexity that is associated with this disease, the therapeutic assessment of a novel inhibitor of YES1 in PDX models of TNBC, and the potential for improving the efficacy of EGFR inhibitors and taxanes in a disease that requires new therapeutic approaches to improve patient outcomes.
Triple Negative Breast Cancer (TNBC) is a highly aggressive disease that has limited treatment options. This proposal focuses on determining if a protein called YES1 may underlie the malignancy associated with TNBC and the molecular pathways it uses to cause poor patient outcomes. This work will also provide a proof-of- concept in model systems testing the possibility of inhibiting YES1 with drugs that may ultimately lead to a more effective approach for treating TNBC.
