Elucidating the Role of TEAD Inhibitors in Triple-Negative Breast Cancer Treatment

Abstract ID 87546 Poster Board 444 Overall, metastasis is a major cause of mortality in cancer patients. Triple-negative breast cancer (TNBC) has the worst prognosis out of all breast cancer subtypes with the highest metastasis rate. In TNBC, almost 50% of patients will have distant metastases. The current standard of care has not progressed from the use of broadly cytotoxic agents such as anthracyclines, taxanes, and platinum agents which are limited by their adverse effects and emerging drug resistance in cancerous tissue. This indicates a significant need for further investigation of understudied drivers of metastatic TNBC to determine new and more selective therapeutic targets. Our lab has shown that metastatic progression and invasion in vitro and in vivo is associated with increased activation of the transcription factor TEAD (TEA family domain member) which is the final nuclear coactivator of the Hippo signaling pathway. The TEAD (1-4) family bind to and are coactivated by YAP/TAZ which are known oncogenes in TNBC. TEADs also bind to the SRC family of transcriptional coactivators that have oncogenic effects in TNBC. Using TEAD inhibitors (TEADi) that prevent TEAD palmitoylation and reduce binding to YAP/TAZ, there is a significant reduction in the invasive capability of TNBC cell lines in 3D sphere models in vitro and reduced lung metastasis in vivo. Furthermore, concurrent TEADi treatment increased sensitivity to doxorubicin treatment in the 4T1 TNBC cell line in vitro. In a pilot experiment in naïve non-tumor bearing mice treated with TEADi, we detected changes in immune cell abundance within the lungs using a transcriptomic analysis, most notably an increase in the alveolar macrophage population. From these observations, I developed the hypothesis that inhibition of TEAD-dependent target genes reduces the primary tumor invasive capability and metastasis through direct effects on tumor epithelium. Furthermore, this is coupled with the anti-metastatic effects of TEADi directly on the tumor niche microenvironment. I further propose that these pleiotropic effects of TEADi will sensitize TNBC to potential combinations with current standard of care (SOC) therapies.