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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) is aggressive, lacking targeted therapies and exhibiting poor survival rates.
• MYCN, an oncogene, is found in various cancers but its role in TNBC is underexplored.
• Identifying novel therapeutic targets for TNBC is critical to improve patient outcomes.

Purpose of the Study:

• To investigate the role and therapeutic implications of MYCN expression in triple-negative breast cancer.
• To identify potential drug targets and combination therapies for MYCN-expressing TNBC.

Main Methods:

• High-throughput chemical screening of TNBC cell lines with varying MYCN expression levels.
• Assessment of sensitivity to bromodomain and extraterminal motif (BET) inhibitors based on MYCN levels.
• In vitro and in vivo evaluation of combined BET and MEK inhibition using cell lines and patient-derived xenograft (PDX) models.

Main Results:

• MYCN is heterogeneously expressed in a significant fraction of primary and recurrent TNBC, particularly in tumors unresponsive to neoadjuvant chemotherapy.
• TNBC cells with higher MYCN expression exhibit increased sensitivity to BET inhibitors.
• Combined BET and MEK inhibition demonstrated synergistic anti-cancer effects in both in vitro and in vivo TNBC models.

Conclusions:

• MYCN expression serves as a predictive biomarker for BET inhibitor sensitivity in TNBC.
• Combination therapy with BET and MEK inhibitors represents a promising preclinical strategy for advanced MYCN-expressing TNBC.
• Further clinical investigation of this combination therapy is warranted for patients with advanced MYCN-expressing TNBC.