Targeting MYCN-expressing triple-negative breast cancer with BET and MEK inhibitors

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.

Ex vivo analysis of DNA repair targeting in extreme rare cutaneous apocrine sweat gland carcinoma

“…Altogether, these results support the concept that BET-bromodomain inhibition promotes HR deficiency through depletion of the DNA double stand break resection protein CtIP (C-terminal binding protein (CtBP) interacting protein] [29]. The results also support that simultaneous inhibition of BET and PARP [22], as well as ATR, especially in context of MYC amplified cancers such as this case [30], might result in a robust synthetic lethality in HR-reduced cancer cells.…”

Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

“…Consistently, the part 2 of COLET study was designed to test the combination of cobimetinib, nab-paclitaxel and atezolizumab, with preliminary signs of activity in the PD-L1-positive population 87 . Recently, the concomitant inhibition of MEK and bromodomain and extraterminal motif (BET) has shown synergistic activity in TNBC preclinical models overexpressing the neuroendocrine-associated oncogene MYCN 88 , providing a rationale to explore this combination in patients with MYCN-positive TNBC.…”

Achieving clinical success with BET inhibitors as anti-cancer agents

“…About half of all recurrent TNBC express high levels of n-MYC. 119 These n-MYC overexpressing cells appear to be quite sensitive to the combination of the MEK inhibitor trametinib with high dose (500 nM) JQ1. This combination effectively repressed the levels of both n-MYC and MYC as well as ERK/MAPK phosphorylation.…”