An ErbB2 splice variant lacking exon 16 drives lung carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Lung cancer is the leading cause of cancer mortality.
• Non-small cell lung cancer (NSCLC) can be driven by receptor tyrosine kinase (RTK) ERBB2 alterations.
• ERBB2 alternative splicing, including exon 16 skipping, is known in breast cancer but its role in other cancers is unexplored.

Purpose of the Study:

• To investigate the role of ERBB2 alternative splicing in human cancers, particularly NSCLC.
• To identify and characterize the oncogenic ERBB2ΔEx16 isoform in lung cancer.

Main Methods:

• Genomic and transcriptomic analysis of NSCLC patient samples.
• Functional studies using immortalized lung epithelial cells.
• Development and analysis of a transgenic mouse model with inducible ERBB2ΔEx16 expression in lung epithelium.

Main Results:

• Elevated ERBB2ΔEx16 expression was found in a subset of NSCLC cases.
• Splicing site mutations and exon 16 deletions were identified in lung tumors and other carcinomas.
• ERBB2ΔEx16 expression transformed lung epithelial cells in vitro.
• Transgenic mice rapidly developed lung adenocarcinomas upon ERBB2ΔEx16 induction.

Conclusions:

• ERBB2ΔEx16 acts as a lung cancer oncogene.
• This ERBB2 isoform has potential clinical significance for a subset of NSCLC patients.
• Further research into ERBB2ΔEx16 as a therapeutic target is warranted.