IDENTIFICATION AND CHARACTERIZATION OF MYCN-EXPRESSING TRIPLE-NEGATIVE BREAST CANCER: IMPLICATIONS FOR THERAPETUIC STRATEGIES

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that does not respond to endocrine therapy or human epidermal growth factor receptor 2 (HER2)-targeted therapies. Individuals with TNBC experience higher rates of relapse and shorter overall survival compared to patients with receptor-positive breast cancer subtypes. Preclinical discoveries are needed to identify, develop, and advance new drug targets to improve outcomes for patients with TNBC. Herein, this dissertation reports that MYCN, an oncogene typically overexpressed in tumors of the central nervous system or with neuroendocrine features, is heterogeneously expressed within a substantial fraction of primary and recurrent TNBC and is expressed in an even higher fraction of TNBC that do not display a pathological complete response after neoadjuvant chemotherapy. High-throughput chemical screens were performed on TNBC cell lines with varying amounts of MYCN expression and determined that cells with elevated expression of MYCN were more sensitive to bromodomain and extra-terminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell line and patient-derived xenograft (PDX) models, respectively. The preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced or recurrent MYCN-expressing TNBC.