PROJECT SUMMARY/ABSTRACT
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.