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BETting on combination treatment
MYCN is a well-known oncogene that plays a role in cancer aggressiveness, but it is typically associated with neuroendocrine cancers. Schafer et al. found a role for MYCN in triple-negative breast cancer, a particularly aggressive form of the disease, and identified a potential intervention. Although there is no standard way to target MYCN directly, the authors determined that a group of experimental drugs called BET inhibitors are effective against triple-negative breast cancers that overexpress MYCN, especially when coupled with the inhibition of MEK, another known oncogene.
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. Here, we report that MYCN, an oncogene typically overexpressed in tumors of the 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 TNBCs that do not display a pathological complete response after neoadjuvant chemotherapy. We performed high-throughput chemical screens on TNBC cell lines with varying amounts of MYCN expression and determined that cells with higher expression of MYCN were more sensitive to bromodomain and extraterminal motif (BET) inhibitors. Combined BET and MEK inhibition resulted in a synergistic decrease in viability, both in vitro and in vivo, using cell lines and patient-derived xenograft (PDX) models. Our preclinical data provide a rationale to advance a combination of BET and MEK inhibitors to clinical investigation for patients with advanced MYCN-expressing TNBC.
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