Identification of TRA2B-DNAH5 fusion as a novel oncogenic driver in human lung squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Lung squamous cell carcinoma (SCC) is a major lung cancer subtype with limited understanding of its oncogenic drivers compared to lung adenocarcinoma (ADC).
• Identifying novel oncogenic drivers is crucial for developing targeted therapies in lung SCC.

Purpose of the Study:

• To identify novel oncogenic drivers in lung squamous cell carcinoma.
• To elucidate the mechanism by which the identified driver promotes tumor progression.
• To explore potential therapeutic strategies targeting this driver.

Main Methods:

• Exon array analyses and molecular profiling to identify gene fusions.
• Functional studies to assess the oncogenic role of the TRA2B-DNAH5 fusion.
• Mechanistic investigations into the downstream signaling pathways (SIRT6-ERK1/2-MMP1 axis).
• In vitro and in vivo experiments to evaluate therapeutic inhibition using selumetinib.

Main Results:

• The TRA2B-DNAH5 gene fusion was identified as a novel oncogenic driver exclusively in lung SCC (3.1% prevalence), absent in lung ADC.
• The TRA2B-DNAH5 fusion promotes malignant progression by regulating the SIRT6-ERK1/2-MMP1 signaling axis.
• Inhibition of ERK1/2 activation with selumetinib effectively suppressed the growth of lung SCC harboring the TRA2B-DNAH5 fusion.

Conclusions:

• The TRA2B-DNAH5 fusion is a significant oncogenic driver in a subset of lung SCC.
• The SIRT6-ERK1/2-MMP1 pathway is critical for the oncogenic activity of this fusion.
• Targeting ERK1/2 activation presents a promising therapeutic strategy for lung SCC patients with TRA2B-DNAH5 fusion.